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Molecular docking of sulfonylureas to the SUR1 receptor
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Molecular docking of sulfonylureas to the SUR1 receptor
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Content
Molecular Docking of Sulfonylureas to the SUR1 Receptor
By
Chentong Sun
A Thesis Presented to the
FACULTY OF THE USC SCHOOL OF PHARMACY
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(PHARMACEUTICAL SCIENCES)
December 2021
Copyright 2021 Chentong Sun
ii
Table of Contents
List of Figures ............................................................................................................ v
List of Tables .......................................................................................................... vii
Abbreviations ......................................................................................................... viii
Abstract .................................................................................................................... ix
1 Chapter 1 - Introduction....................................................................................... 1
1.1 Molecular Docking ........................................................................................................... 1
1.2 SUR1 Receptor ................................................................................................................. 4
1.3 Sulfonylureas .................................................................................................................... 7
2 Chapter 2 - Methods ..........................................................................................12
2.1 Preparing Glibenclamide ................................................................................................ 12
2.2 Preparing Other Sulfonylureas ....................................................................................... 13
2.3 Adding Charges .............................................................................................................. 13
2.4 Autodock ........................................................................................................................ 14
2.5 Grouping of Sulfonylureas ............................................................................................. 16
2.6 Solvation......................................................................................................................... 17
2.7 Analysis .......................................................................................................................... 19
2.8 Finding Hydrogen Bonds ............................................................................................... 20
3 Chapter 3 – Glibenclamide ................................................................................21
iii
3.1 Starting Structure for Molecular Docking ...................................................................... 21
3.2 Best Docking Pose without Solvation ............................................................................ 23
3.3 Best Docking Pose after Solvation ................................................................................. 25
3.4 Deprotonation Site of Glibenclamide ............................................................................. 29
3.4.1 Deprotonation on N1............................................................................................... 30
3.4.2 Deprotonation on N2............................................................................................... 32
3.4.3 Standard Structure with Protonation on N1 and N2 ............................................... 34
4 Chapter 4 – Other Sulfonylureas .......................................................................36
4.1 Glipizide ......................................................................................................................... 36
4.2 Glimepiride..................................................................................................................... 40
4.3 Gliclazide ....................................................................................................................... 42
5 Chapter 5 - Discussions .....................................................................................47
5.1 Binding of Glibenclamide .............................................................................................. 47
5.2 Binding of Glipizide ....................................................................................................... 49
5.3 Binding pattern of Glimepiride ...................................................................................... 51
5.4 Binding pattern of Gliclazide ......................................................................................... 53
5.5 Ranking of Sulfonylureas Activities .............................................................................. 55
5.6 Limitation of the study and further research .................................................................. 57
References ................................................................................................................59
iv
Appendix ..................................................................................................................62
Appendix A: Standard glibenclamide ....................................................................................... 62
Appendix B: Glibenclamide with N1 deprotonation ................................................................ 65
Appendix C: Glibenclamide with N2 deprotonation ................................................................ 68
Appendix D: Edited N2 deprotonated glibenclamide ............................................................... 71
Appendix E: Gliclazide ............................................................................................................. 74
Appendix F: Glimepiride .......................................................................................................... 76
Appendix G: Glipizide .............................................................................................................. 78
v
List of Figures
Figure 1-1. Structure of Isoniazid. .................................................................................................. 2
Figure 1-2. Potential InhA inhibitors selected by molecular docking. ........................................... 3
Figure 1-3. Structure of KATP Complex. ......................................................................................... 5
Figure 1-4. Structure of SUR1. ....................................................................................................... 5
Figure 1-5. Function of KATP channel in insulin regulation. ........................................................... 7
Figure 1-6. The common part of sulfonylureas.. ............................................................................ 8
Figure 1-7. Structures of sulfonylureas ........................................................................................... 9
Figure 1-8. IC50 of sulfonylureas against SUR1, SUR2A and SUR2B receptors. ..................... 11
Figure 2-1. Crystal structure of the SUR1- glibenclamide complex. ........................................... 12
Figure 2-2. Common part of sulfonylureas ................................................................................... 13
Figure 2-3. Setup of adding charges ............................................................................................. 14
Figure 2-4. Setup of Dock Prep and AutoDock Vina ................................................................... 15
Figure 2-5. Four groups of glibenclamide poses. ......................................................................... 17
Figure 2-6. Setup of Solvate_GUI ................................................................................................ 18
Figure 2-7. Setup of searching hydrogen bonds. .......................................................................... 20
Figure 3-1 Starting structures of two groups ................................................................................ 22
Figure 3-2. Poses 41,42 and 51. ................................................................................................... 25
Figure 3-3. RMSD vs. ΔG plot for four groups and the standard structure. ................................. 28
Figure 3-4. Structure of Pose 16 after solvation. .......................................................................... 29
Figure 3-5. RMSD vs. ΔG plot for three groups and the standard structure. ............................... 32
Figure 3-6. RMSD vs. ΔG plot for four groups and the standard structure. ................................. 34
Figure 4-1. Four groups for glipizide. ........................................................................................... 38
vi
Figure 4-2. RMSD vs. ΔG plot for four groups and the standard structure. ................................. 39
Figure 4-3. Pre-solvated ΔG vs. post-solvated Δ G for each pose. ............................................... 40
Figure 4-4. RMSD vs. ΔG plot for four groups and the standard structure. ................................. 42
Figure 4-5. All five poses in Group 3 and the standard structure. ................................................ 43
Figure 4-6. RMSD vs. ΔG plot for four groups. ........................................................................... 45
Figure 4-7. The top 6 poses of gliclazide in SUR1. ...................................................................... 45
Figure 4-8. Pre-solvated ΔG vs. post-solvated Δ G for each pose. ............................................... 46
Figure 5-1. Binding of Pose 36 without water molecules. ............................................................ 48
Figure 5-2. Binding of Pose 36 with water molecules. ................................................................. 49
Figure 5-3. Binding of Pose 50 without water molecules. ............................................................ 50
Figure 5-4. Binding of Pose 50 with water molecules. ................................................................. 51
Figure 5-5. Binding of Pose 13 without water molecules. ............................................................ 52
Figure 5-6. Binding of Pose 13 with water molecules. ................................................................. 53
Figure 5-7. Binding of Pose 8 without water molecules. .............................................................. 54
Figure 5-8. Binding of Pose 8 with water molecules. ................................................................... 54
Figure 5-9. Significant residues for each molecule and shared residues among four molecules. 55
vii
List of Tables
Table 1-1. Physical property of sulfonylureas .............................................................................. 10
Table 3-1. Average RMSD and binding score for the crystal and PubChem groups ................... 23
Table 3-2. Docking results for Glibenclamide without solvation. ................................................ 23
Table 3-3. Number of water molecules and ΔG of different layers of solvation. ......................... 26
Table 3-4. RMSD and ΔG for four groups after solvation. .......................................................... 27
Table 3-5. Experimental and calculated pKa of sulfonylureas ..................................................... 30
Table 3-6. Charge on N1 and N2 when both hydrogens were deprotonated ................................ 30
Table 3-7. Free energy and ΔG of N1 deprotonated glibenclamide ............................................. 31
Table 3-8. Free energy and ΔG of N2 deprotonated glibenclamide ............................................. 33
Table 3-9. Free energy of four trials before solvation .................................................................. 35
Table 3-10. Free energy of four trials after solvation. .................................................................. 35
Table 4-1. Average RMSD and ΔG for the four groups of glipizide............................................ 37
Table 4-2. Average RMSD and ΔG for each group. ..................................................................... 41
Table 4-3. Average RMSD and ΔG for each group. ..................................................................... 44
Table 5-1. Free energy of four sulfonylureas. ............................................................................... 56
viii
Abbreviations
ABC: ATP-binding cassette
CADD: Computer-aided drug design
ΔG: Gibbs free energy
IC50: Half-maximal inhibitory concentration
KATP: ATP-sensitive potassium channel
Ki: Inhibition constant
NDB: Nucleotide-binding domain
PDB: Protein Data Bank
pKa: Logarithmic dissociation constant
RMSD: Root-mean-square deviation of atomic positions
SUR1: Sulfonylurea receptor 1
TMD: Transmembrane domain
VGCC: Voltage-gated calcium channel
ix
Abstract
Molecular docking is a powerful tool in drug discovery. It intuitively presents invisible
bonds and atoms in a visible way so that it makes the drug discovery more efficient and
affordable. In recent years, it has become one of the most commonly used methods in drug
discovery. Drug design has shifted from a tool purely focusing on molecular interactions to a
platform to study both pharmacodynamics and pharmacokinetic properties. In this research,
molecular docking was performed to study ligand binding to sulfonylurea receptor 1 (SUR1),
which is a regulatory subunit of the ATP-binding cassette (ABC) transporter. The abnormal
activity of SUR1 is closely related to congenital hyperinsulinism and type 2 diabetes.
Glibenclamide is a typical example of a sulfonylurea inhibitor of SUR1, and it is the only ligand
with an available X-ray structure with SUR1. The research started from the molecular docking of
glibenclamide and extended to other drugs in the sulfonylurea family. The binding energy of
SUR-ligand complexes was calculated in both solvated and un-solvated states, and common
characters of low free energy complexes were examined. The purpose of this research is to
understand the most favorable conformation of sulfonylureas in the complex, discover the
binding pattern of SUR1 - ligand complexes, and explore the energy calculations in solvated
molecular docking.
1
1 Chapter 1 - Introduction
1.1 Molecular Docking
In modern pharmaceutical industry, computer-aided drug design (CADD) is getting
increasing attention. Unlike experimental methods, such as high-throughput screening, a real
compound is not necessary for a virtual approach of drug discovery, so it is more efficient and
affordable. Molecular docking is an in-silico method for simulating the interactions between a
ligand and its receptor. It is the most common and essential tool in CADD.
In 1975, molecular docking emerged as a tool in parallel with high-throughput protein
purification X-ray crystallography and nuclear magnetic resonance spectroscopy to visualize the
receptor–ligand complexes. The core algorithm was to calculate the best geometrically
complementary shapes as rigid bodies and select the best pose based on the free energy
1
. Since
then, the performance and function of molecular docking have been improved through
optimization of the algorithm and hardware. In 1982, Kuntz introduced a shape matching
algorithm focusing on the geometric distance between the ligand and the receptor
2
. Thereafter, a
new algorithm based on Fourier transformation was prevalent, that facilitated the calculation by
digitalizing the molecules
1
. Nowadays, there are generally two types of conformational search
algorithms. Systematic search algorithms include eHiTS, FRED, Surflex-Dock, DOCK, GLIDE,
EUDOC, FlexX, Hammerhead, Flog, SLIDE and ADAM. Random search algorithms include
AutoDock, Gold, PRO_LEADS, EADock, ICM, LigandFit, Molegro Virtual Docker, CDocker,
GlamDock, PLANTS, MOLDock and MOE_Dock
3
.
As a versatile and practical tool, molecular docking is playing a significant role in drug
discovery. It is commonly applied to target fishing and profiling, adverse effect prediction,
2
virtual screening, polypharmacology, binding rationalization and drug repositioning
4
. Moreover,
there are multiple examples of applying molecular docking in drug discovery. Isonicotinic-acyl-
NADH complex is an InhA Inhibitor for treating tuberculosis. The drug was derived from
isoniazid, which is shown in Figure 1-1. The process of isonicotinic-acyl-NADH discovery
started from analyzing the receptor. A crystallographic structure of InhA was obtained from the
Protein Data Bank (PDB). Candidate molecules in the ZINC database were filtered based on the
property required by the binding site, including log P, number of rotational bonds, number of
hydrogen bond acceptor, polar surface area and molecular weight. Multiple docking programs
were used to run virtual screening and score each molecule. The top scored molecules were
selected as starting points of further research (Figure 1-2)
5
. In addition, application of molecular
docking has also played a significant role in the discovery of proteasome inhibitors, STAT3
inhibitors, Pim-1 kinase inhibitors, aldose reductase inhibitors and selective cyclooxygenase-2
inhibitors
3
.
Figure 1-1. Structure of Isoniazid.
3
Figure 1-2. Potential InhA inhibitors selected by molecular docking
3
In this research, UCSF Chimera was used as the visualization platform for molecular
docking. This program was developed by UCSF in 2004
6
. It allows users to visualize, edit, move
and analyze a molecule. The source of molecules can be the PDB, which is a database for 3D
structures of proteins, nucleic acids, and complexes. To date, 177910 protein structures, 52564
structures of human sequences, and 12984 nucleic acid containing structures have been recorded
in the database
7
.
AutoDock Vina is a program for molecular docking and virtual screening. AutoDock Vina
was developed by Trott and Olson in 2011. It uses an iterated local search optimizer to randomly
search the torsion for every rotatable bond, so that it can build different conformations for a
ligand. Empirical scoring functions allowed the program to calculate the free energy of the
complex. The calculation takes both intermolecular and intramolecular factors into account,
which includes hydrogen bonds, rotational bonds, hydrophobics and repulsion. Another
important function of AutoDock Vina is to calculate the root-mean-square deviation of atomic
positions (RMSD) between two conformations using Equation 1.1
8
.
4
𝑅𝑀𝑆𝐷 = √
1
𝑛 ∑ 𝑟 𝑖 2 𝑛 𝑖 =1
(Equation. 1.1)
where n = number of atoms in each molecule; r = distance between two matched atoms.
1.2 SUR1 Receptor
ATP-sensitive potassium channel (KATP) is an ATP-binding cassette (ABC) transporter
located in the cell membrane. It allows potassium ions to unidirectionally flow out of the cell.
KATP is an octameric complex with four structural Kir6.2 subunits and four regulatory subunits
(Figure 1-3). In a pancreatic β-cell, the regulatory subunit is the sulfonylurea receptor 1 (SUR1),
which is the main receptor discussed in this study. In adipose tissue or muscle cells, the
regulatory subunit is SUR2A or SUR2B. Four Kir6.2 subunits form a channel to allow to K
+
move through, and SUR1 is a regulatory subunit to control the activity of the channel. Figure 1-4
shows the structure of the SUR1 receptor. A SUR1 subunit has five domains including 3
transmembrane domains (TMDs) and 2 nucleotide-binding domains (NDBs). On each NDB
there is a binding site for ATP or ADP. There is an additional binding site between two TMDs,
which is for sulfonylureas. KATP channel will close when an ATP molecule binds to the SUR1
receptor, and it is active when an ADP molecule binds to the binding site
9
.
5
Figure 1-3. Structure of KATP Complex. Kir6.2 subunits are in white color, and SUR1 subunits
are in blue. The structure was obtained from PDB as 5WUA
10
and the image was edited by
Chimera 1.14
6
.
Figure 1-4. Structure of SUR1. Three TMDs are shown in gray, and two NBDs are highlighted in
yellow. The left end of the receptor is named the closing end, and the right end is the opening
end. The structure was obtained from PDB as 6PZI
11
, and the image was edited by Chimera
1.14
6
.
6
KATP is an important therapeutic target for diabetes treatment because it is closely related to
secretion of insulin (Figure 1-5). In a normal pancreatic β-cell, when the glucose concentration in
blood increases, more ATP molecules are synthesized from ADP through the glycolysis
pathway. As an ATP molecule binds with SUR1 receptor, the KATP channel is blocked. K
+
ions
are not able to move out of the cell, so that the cell membrane is depolarized. In the depolarized
state, voltage-gated calcium channels (VGCC) allow Ca
2+
ions to move into the cell, which
promotes the secretion of insulin. When the glucose level is low, in contrast, the ADP
concentration is relatively higher, which activates the KATP channel and keeps the membrane
polarized. A closed VGCC inhibits Ca
2+
moving into the cell, so that secretion of insulin is
blocked
12
. A SUR1 mutation can interfere with the KATP response to ATP or ADP. A loss of
function mutation on SUR1 causes hyperinsulinism. A lower level of ATP cannot normally
activate the channel, so the membrane is constantly depolarized. Ca
2+
ions continuously enter the
cell, which cause constant insulin release. When SUR1 has a gain of function mutation, a high
level of ATP cannot block the channel normally, so the β-cell responds as in the low metabolism
condition, and the low level of insulin secretion causes diabetes
9
.
7
Figure 1-5. Function of KATP channel in insulin regulation. (a) A normal β-cell in the low
metabolism condition. (b) A normal β-cell in the high metabolism condition. (c) A β-cell with
hyperinsulinism caused by a loss-of-function mutation in SUR1. (d) A β-cell with neonatal
diabetes caused by a gain-of-function mutation in SUR1.
1.3 Sulfonylureas
Sulfonylureas are a class of drug with a phenylsulfonylurea group (Figure 1-6), which is
common among all the sulfonylureas. The two nitrogen atoms were referred to as N1 and N2 for
convenience in this thesis, as shown in Figure 1-6. The various groups on N1 are much larger
than those on N2. The bond between the urea carbon and N1 is more stable due to strong
resonance
13, 14
. The resonance confers the bond some double bond character and prevents it from
rotating freely. Therefore, only the bond between the urea carbon and N2 is rotatable. The
8
phenylsulfonylurea group could have two conformations based on the torsion of the C-N2 bond.
They could be either trans or cis. In solid state, the urea group prefers a trans conformation, so
they are closely arranged, and form the crystal with the lowest entropy. However, sulfonylurea
has a cis conformation in solution. A larger distance between sulfonylureas allow water
molecules to insert in and form the most stable structure. Therefore, when glibenclamide binds
to SUR1 in the physiological environment, a cis-glibenclamide is more favorable.
Figure 1-6. Common part of sulfonylureas. Sulfonylurea group was highlighted in red color. R
1
and R
2
were various groups. Two urea nitrogen atoms were names N1 and N2, respectively.
A sulfonylurea is an inhibitor for SUR1 receptor. It noncompetitively binds to SUR1 at an
allosteric site and causes a conformational change in the receptor that result in the KATP channel
being blocked. A depolarized membrane allows Ca
2+
to enter the β-cell, and promotes insulin
secretion
15
. This mechanism allows sulfonylureas to be drugs for treating type 2 diabetes.
9
Figure 1-7. Structures of sulfonylureas
In this study, the binding affinity of glibenclamide, gliclazide, glimepiride and glipizide
were assessed by molecular docking (Figure 1-7). Table 1-1 presents the physical properties of
the four molecules
16-19
. Glibenclamide and glimepiride are the larger molecules among the four
and gliclazide is the smallest. All except gliclazide have 3 hydrogen bond donors. Glipizide has
the most hydrogen bond acceptors at 6. Glibenclamide and glimepiride both have 5, and
gliclazide only has 3. The number of rotational bonds is crucial to the free energy calculation
because it determines the flexibility of the molecule. Glibenclamide has the most rotational
bonds at 8. Glimepiride and glipizide both have 7 rotational bonds, and gliclazide only has 3. All
four sulfonylureas have a positive logP, which means that they are hydrophobic. Polar surface
area is an important indicator of the ability to cross the membrane. Only gliclazide has a polar
surface area less than 90 Ų, so it is the only one that can cross the blood–brain barrier, and act in
the central nervous system
20
.
10
Table 1-1. Physical property of sulfonylureas
Molecule Molecular
Weight
(Da)
Hydrogen
Bond
Donor
Hydrogen
Bond
Acceptor
Rotational
Bonds
Log P Polar
Surface
Area (Ų)
Glibenclamide 494 3 5 8 4.8 122
Gliclazide 323 2 4 3 1.5 86.9
Glimepiride 490 3 5 7 3.9 133
Glipizide 446 3 6 7 1.9 139
The half-maximal inhibitory concentrations (IC50) are shown in Figure 1-8. Glibenclamide
is the most common sulfonylurea and is the mainly focus in this study. Glibenclamide needs the
lowest concentration to achieve a 50% inhibition effect, so it is considered the most powerful
sulfonylurea. Besides, since sulfonylureas are noncompetitive inhibitors of SUR1, its IC50 is
equal to its inhibition constant (Ki)
21
. Therefore, glibenclamide also has the highest affinity with
SUR1 receptor, and its pKi is about 10.7. Glimepiride and glipizide bind with SUR1 with a
similar affinity. Their pKis are about 8.8 and 8.7, respectively. Gliclazide has the highest IC50,
and it also has the lowest affinity for the receptor, with a pKi about 7.9
22
.
11
Figure 1-8. IC50 of sulfonylureas against SUR1, SUR2A and SUR2B receptors
22
. Data from
multiple resources are collected and shown in the figure. Molecules in interested are highlighted
in red box.
12
2 Chapter 2 - Methods
2.1 Preparing Glibenclamide
The standard crystal model of the SUR1-glibenclamide complex was obtained from the
PDB as 5YW7
23
. The structure was viewed and prepared in Chimera 1.14
6
. As shown in Figure
2-1, the structure contains a SUR1 receptor, a glibenclamide molecule, and an ATP molecule. In
order to get a pure receptor, the ATP and glibenclamide were removed from the structure, and
the rest was saved as a pure receptor. The receptor and ATP were removed to get a pure
glibenclamide model. The “AddH” function in Chimera was used to add the hydrogens in the
glibenclamide structure. Another random glibenclamide structure was acquired from PubChem
as CID 3488
19
.
Figure 2-1. Crystal structure of the SUR1- glibenclamide complex. The SUR1 receptor is shown
in brown, and the glibenclamide and the ATP are highlighted in green. The structure was
obtained from the PDB as 5YW7
23
and the image was edited by Chimera 1.14
6
.
13
2.2 Preparing Other Sulfonylureas
In order to have a constant and standard sulfonylurea backbone for all sulfonylurea drugs,
the structures of other sulfonylureas were obtained by editing the standard glibenclamide
structure using the “Structure Editing” tool in Chimera. The substituents on the phenyl ring and
urea were deleted. The rest of the molecule is universally shared in all sulfonylureas (Figure 2-
2). The various groups of gliclazide, glimepiride, and glipizide were added to the backbone.
Figure 2-2. Common part of sulfonylureas
2.3 Adding Charges
The pure glibenclamide model with hydrogens was opened in Chimera. The hydrogen on
N1 or N2 was then deleted. The function of “add charge” was used
24
as shown in Figure 2-3.
When one hydrogen atom was deleted, the net charge was -1, and when both hydrogens on N1
14
and N2 were deleted, the net charge was -2. Enabling “show charges to atom”, the charge value
of every atom in the molecule was calculated.
Figure 2-3. Setup of adding charges
2.4 Autodock
Both receptor and ligand were opened together in Chimera. “Dock Prep” in chimera was
used to prepare the receptor for docking by deleting solvent and non-complexed ions, adding
charges and hydrogens, replacing incomplete side chains, and converting modified amino acids
to standard amino amides
25
. AutoDock Vina 1.1.2 was used for docking after preparation
8
. The
location of the binding site was determined by X-ray crystallography of glibenclamide, and all
other sulfonylureas were assumed to bind to SUR1 at the same location. A search box located at
(200, 220, 180), with a size of 27× 22× 37 was used for glibenclamide, glipizide and glimepiride.
15
Gliclazide is the smallest ligand among these four, so a smaller box with a size of 17× 22× 22 was
set at the same location. The detailed setup was shown in Figure 2-4.
Figure 2-4. Setup of Dock Prep and AutoDock Vina
16
2.5 Grouping of Sulfonylureas
All docking poses were generated by AutoDock Vina 1.1.2 from the starting structure.
Poses 1 to 10 were the first-generation poses generated from the standard structure. Poses 11 to
20 were the second-generation poses generated from Pose 1, and so on in a similar manner.
Docking poses of glibenclamide were sorted into 4 groups based on the position and
orientation of the common shared group. Group 1 included those poses having their common
shared group located at the closing end of the binding pocket. Poses in Group 2 have their
sulfonylurea group located in the middle of the binding pocket, and the urea oxygen pointed
downward to ASN1245. In Group 3, the sulfonylurea group is also located in the middle of the
binding pocket as well, but the urea oxygen pointed to ARG1246. Molecules in Group 4 have
their sulfonylurea group located at the opening end of the binding pocket. Examples of the 4
groups are shown in Figure 2-5.
For other sulfonylureas, poses were sorted into 4 groups based on the relative position
compared to the glibenclamide poses. Group 1 included poses with the sulfonylurea group out of
the projected binding pocket of glibenclamide. Group 2 had poses that were in the binding
pocket of glibenclamide and pointing to the same direction as the standard structure of
glibenclamide, but not belonging to Group 3. Group 3 included poses in the same sulfonylurea
conformation with the crystal structure of glibenclamide. Group 4 was for all other poses in the
binding site but in an inverse direction.
17
Figure 2-5. Four groups of glibenclamide. The image were edited using Chimera 1.14
6
.
2.6 Solvation
Watgen 5.02 was used to add water molecules to the docked SUR1-ligand complexes and
Solvate_GUI was used as the platform for collection and analyzing data. The pdb file of pure
SUR1 receptor and the pdbqt files of docking poses were used by the program. The setup of the
program is shown in Figure 2-6. Five layers of water molecules were added in the complex by
Watgen 5.02. Data for water molecules, hydrogen bonds, distances between atoms and energy
were collected automatically by Solvate_GUI. An Excel file with these data was generated. The
molar Gibbs free energy was calculated using Equation 2.1.
∆𝐺 = (−2 ∗ 𝐴 ) + (2 ∗ 𝐵 ) + 𝐶 + (−2 ∗ 𝐷 ) + (2 ∗ 𝐸 ) + (1 ∗ 𝐹 ) + (0.2 ∗ 𝐺 )
(Equation 2.1)
18
where A = number of protein-ligand hydrogen bonds; B=number of broken hydrogen
bond due to solvation; C = number of same charge atom clashes; D = number of displaced
water molecules due to direct contact to the ligand; E = number of trapped water
molecules; F = number of rotational bonds. G = number of displaced water molecules
In the equation, assumptions were made on the standard enthalpy. A hydrogen bond and a
displaced water were considered to be -2 kcal/mol. A rotational bond and a same charge atom
clash were considered to be 1 kcal/mol. Since Autodock Vina uses different parameters, the
value of ΔG cannot be compared directly between the two programs.
Figure 2-6. Setup of Solvate_GUI
19
2.7 Analysis
The results of docking provided the binding score and RMSDs compared to the highest
score pose. The binding score is the free energy of the complex in the unit of kcal/mol. This can
be converted into pKd based on Equation 2.2.
∆𝐺 = 𝑅𝑇 𝑙𝑛 𝐾𝑑 (Equation 2.2)
where ∆G = molar Gibbs free energy, J/mol; R = ideal gas constant, 8.314 J/mol/K; T =
temperature, K; Kd = equilibrium constant.
Moreover, a RMSD calculation was used to evaluate the conformational and positional
difference between the docking poses and the starting structures. For obtaining a RMSD only
count conformational difference, all the poses were opened along with the standard structure in
PyMOL 2.4.1. The function of align in PyMOL was used to calculate the RMSD of these
molecules by input Command 1. For calculating a RMSD considering both conformational
𝑎𝑙𝑖𝑔𝑛 1, 2, 𝑐𝑦𝑐 𝑙 𝑒𝑠 = 0, 𝑡𝑟𝑎𝑛𝑠𝑓𝑜𝑟𝑚 = 0 (Command 1)
where “1” = name of the first molecule; “2” = name of the second molecule
and positional difference, poses were opened in Chimera 1.14, and Command 2 were inputted.
𝑟𝑚𝑠𝑑 #1 #2 (Command 2)
where “1” = name of the first molecule; “2” = name of the second molecule
A t-test was performed in Microsoft Excel when necessary to prove a statistically
difference between two sets of data. A p-value lower than 5% indicated strong evidence that a
difference existed.
20
2.8 Finding Hydrogen Bonds
The ligand and receptor was opened in Chimera 1.14. The function “FindHBond” was used
to show possible hydrogen bonds. Since the hydrogen bonds between the ligand and receptor
were wanted, only the ligand was selected in the interface. An option allows users to display
hydrogen bonds related to the selected model. The detailed setup is shown in Figure 2-7.
Figure 2-7. Setup of searching hydrogen bonds.
21
3 Chapter 3 – Glibenclamide
Glibenclamide was chosen as a representative sulfonylurea because a structure with SUR1
obtained from X-Ray crystallography was available. This was used as a standard for determining
the position of binding site. The purpose of the chapter is to set the parameter for molecular
docking, explore the rationality of molecular docking, determine the most likely conformation of
glibenclamide, and discover the binding pattern of glibenclamide.
3.1 Starting Structure for Molecular Docking
During docking in prior research, a high scoring starting structure was found more likely to
generate high scored docking poses, and a low scored structure usually generated a set of poses
that also had a low score. Therefore, autodocking poses were closely related to their starting
structure although conformations and positions were adjusted automatically by the program. In
order to pick a standard conformation of glibenclamide, two different conformations of
glibenclamide were tested.
The first starting structure used was structure 3488 from PubChem
19
, and second one was
the glibenclamide molecule from the crystal structure of glibenclamide-SUR1 complex. Their
structures are shown in Figure 3-1. The PubChem structure has a trans urea conformation, and
the crystal structure has a cis conformation. The better performing conformation was picked as
the standard structure.
22
Figure 3-1 Starting structures of two groups
Since the PubChem structure did not bind to the receptor in the model, it was not in the
most favorable position in the binding site as the preferred conformation. On the contrary, the
crystal structure was poised to bind with the receptor. The hypothesis was that the crystal
structure generated better docking poses than the PubChem structure.
Two glibenclamide models with different conformations were used as the starting
structures in the PubChem and the Crystal groups. A total of 60 docking poses were generated
from each starting structure following the methods in Chapter2, and their docking scores were
recorded. The RMSD for the conformational differences was calculated compared to the starting
structures.
Table 3-1 shows the result of RMSD and binding score comparison. In the Crystal group,
docking poses had a statistically significantly lower RMSD compared to their starting structure
than comparing to the PubChem structure. Docking poses in the PubChem group had a similar
23
conformation to PubChem structure. Moreover, the Crystal group had a better binding affinity to
SUR1 receptor. The docking poses had a better average ΔG than the poses in the PubChem
gtroup of -8.9 kcal/mole versus -8.5 kcal/mol. The results agreed with the hypothesis that the
crystal structure would perform better in docking. In order to obtain better docking poses in the
following work, the crystal structure was selected as the standard structure for glibenclamide.
Table 3-1. Average RMSD and binding score for the crystal and PubChem groups
Group
RMSD to Crystal
Structure
RMSD to PubChem
Structure
Binding Score
(kcal/mol)
Crystal 3.151 5.089 -8.9
PubChem 5.014 3.468 -8.5
3.2 Best Docking Pose without Solvation
The standard structure and all the docking poses were distributed into four groups
following the method in Chapter 2. The standard structure was supposed to have the best binding
score because the structure was directly obtained from the SUR1- glibenclamide complex. The
standard structure was in Group 3, so Group 3 was hypothesized to have the best binding poses.
Table 3-2. Docking results for Glibenclamide without solvation.
Group Number Average RMSD ΔG (kcal/mol)
1 20 9.7 -8.7
2 18 3.8 -9.1*
3 18 3.6 -8.9*
4 4 4.4* -8.6
Total 60 5.7 -8.9
* Statistically significant difference with the following higher group, as the RMSD of Group 3
compared to the RMSD of Group 2.
24
The 60 docking poses were distributed into four groups as shown in Table 3-2. Most
poses were located in the middle of the binding pocket, one-third were at the closing end, and
just a few poses were close to the opening end. RMSD reflected both conformational and
positional difference between poses and standard structure. Group 3 had the lowest average
RMSD value, which was 3.6, and it was followed by Group 2 with a RMSD of 3.8. Group 4 had
a slightly higher RMSD of 4.4. Finally, poses in group 1 had the largest difference, and its
RMSD was 9.7.
A t-test was performed for adjacent ranking groups. For RMSD data, only Group 4 had a
statistically significant difference with its following group, which was Group 1. The P-value
revealed that the conformations of poses in groups 2, 3 and 4 were basically similar. The binding
score of a docking pose revealed how well a ligand binds to its receptor. Group 2 had the lowest
binding score of all groups, which was -9.1 kcal/mol. It was slightly lower than group 3, which
was -8.9 kcal/mol, but a p-value of 0.002 indicated that they are significantly different. Group 3
was followed by Group 1, which is -8.7 kcal/mol. A t-test suggested that the 0.2 kcal/mole gap
was also significant. Group 4 had the highest binding energy, which represented the worst
binding affinity, and a t-test suggested its difference with Group 1 was not significant.
The best scored poses of glibenclamide before solvation were poses 41, 42 and 51. They
were all from group 2. In Figure 3-2, three poses were aligned together. Poses 41 and 51
basically overlapped, and their RMSD was 0.463. The two poses were close to Pose 42 as well.
The RMSD between poses 41 and 42 was 1.605, and that between pose 51 and 42 was 1.667.
Group 2 had both the lowest scoring individual poses from all 60 poses and the lowest
average free energy among the four groups. Therefore, it was reasonable to consider Group 2 as
25
the best binding group. The result disproved the hypothesis, and the conformation of Group 2
should represent the best binding pattern in the SUR1 receptor without solvation.
Figure 3-2. Poses 41,42 and 51. The green structure is Pose 41, the purple structure is Pose 42,
and the blue structure is Pose 51.
3.3 Best Docking Pose after Solvation
In Section 3.2, a sufficient number of trials ensured that poses in all possible positions and
conformations were generated. However, AutoDock Vina operates without explicit water
molecules in the binding site. This assumption may explain why ΔG did not indicate Group 3 as
the highest affinity group. However, in physiological condition, SUR1 and glibenclamide are
definitely solvated. Therefore, it is necessary to reevaluate the free energy of autodocking poses
after solvation.
26
Solvation inserted water molecules between the receptor and ligand. This could change the
free energy of the receptor-ligand complex by breaking extant hydrogen bonds between ligand
and receptor, and reforming new hydrogen bonds through water molecules. Moreover, compared
with a pure solvated receptor, in a receptor–ligand complex, displacement of water molecules
caused by the ligand could also be a factor in the free energy difference. Free energy after
solvation was considered to better represent the binding affinity in the physiological
environment. Therefore, Group 3 was hypothesized to have the best binding score after
solvation.
An option in Solvate_GUI allows users to select the layers of water in solvation. An
inadequate number of water molecules could influence the final result, and excessive layers of
water extend the computer time without improving the result. Therefore, a reasonable choice of
the number of layers is important for the program.
Table 3-3. Number of water molecules and ΔG of different layers of solvation.
Layers of Water Ligand Waters Receptor Waters Complex Waters
Calculated ΔG
(kcal/mol)
3 105 404 384 -23
5 312 428 405 -21.4
7 563 428 405 -21.4
9 758 428 405 -21.4
The standard glibenclamide structure was used to run solvation with the pure SUR1
receptor. A choice of 3, 5, 7, and 9 layers of water molecules were added into the complex. The
results are shown in Table 3-3. Adding more layers of water constantly increased the number of
water molecules around the ligand. On the contrary, the number of water molecules within the
receptor or complex did not increase after reaching a maximum, which indicated that the
27
receptor was already filled by water molecules. Moreover, the calculated free energy remained
steady after reaching the limit. The results indicated that 5 layers of water molecules were
enough to fill the receptor. The limitation was receptor dependent, but not ligand dependent.
Therefore, 5 layers were used for all sulfonylureas in the following works. In addition, the trial
also determined the solvated ΔG of the standard glibenclamide model, which was -21.4 kcal/mol.
Table 3-4. RMSD and ΔG for four groups after solvation.
Group Number Average RMSD
Average ΔG
(kcal/mol)
Maximum ΔG
(kcal/mol)
Minimum ΔG
(kcal/mol)
1 20 9.7 -7.2
8 -20
2 18 3.8 -17.0*
-9.4 -22.8
3 18 3.6 -19.4
-5.2 -27.2
4 4 4.4 -8.8
-0.2 -16
Total 60 5.7 -13.9
8 -27.2
Sixty docking poses were solvated with SUR1 using Solvate_GUI (Table 3-4). Unlike the
results without solvation, Group 3 had the best average binding affinity to the receptor, with an
average ΔG of -19.4 kcal/mol. Group 2 closely followed Group 3, with a ΔG of -17 kcal/mol.
There was a huge gap between Group 2 and Group 4, so poses in Group 4 and Group 1 did not
bind as well as those in Group 2 and Group 3. All the poses including the crystal structure are
plotted in Figure 3-3. The average RMSD and ΔG divided the plot into four quadrants. In the
first quadrant, poses had a high RMSD and a poor binding affinity. Poses in Group 1 were
centralized in this quadrant. Poses in the second quadrant had a similar conformation with the
standard structure, but they had a poor affinity to the receptor. Group 4 was concentrated in this
quadrant. The third quadrant included poses with high affinity and positions similar to the crystal
structure. Both Group 2 and 3 accumulated in the third quadrant, which indicated that Group 2
and Group 3 had a high affinity to SUR1 receptor after solvation. Group 3 was even closer to the
28
left-bottom corner than Group 2, and four of the five lowest ΔG values were from poses in
Group 3.
Figure 3-3. RMSD vs. ΔG plot for four groups and the standard structure. Points from Group 1,
2, 3, 4 and the crystal structure were shown in red, yellow, green, blue and purple, respectively.
The horizontal and vertical blue lines represent the average ΔG and RMSD, which are -13.9 and
5.7, respectively.
The lowest ΔG was from Pose 16 from Group 3, which was -27.2 kcal/mol (Figure 3-4).
This pose had 8 direct protein-ligand hydrogen bonds, and 16 single water bridges. A total of 28
connections between ligand and SUR1 was the most within all the poses. There were a total of 9
poses with a lower ΔG than the solvated standard structure. Eight of these poses were from
Group 3. The calculated ΔG results support the hypothesis that Group 3 had the best binding
affinity to SUR1 after solvation.
29
Figure 3-4. Structure of Pose 16 after solvation. Pose 16 is shown in blue color, and the receptor
is in gray. Only the inner layer of water is shown in the figure.
3.4 Deprotonation Site of Glibenclamide
In a sulfonylurea, there are two possible sites for deprotonation, which are the hydrogen
atoms at N1 or N2. The logarithmic dissociation constant (pKa) of sulfonylureas is around 6, and
more than 96% of molecules are ionized in plasma
26, 27
(Table 3-5). The dissociation data
indicated that only one pKa is observed for each molecule. Therefore, only one of the nitrogen
atoms is protonated. An ionized nitrogen may have a significant effect on binding, so it is
necessary to understand the site of protonation.
30
Table 3-5. Experimental and calculated pKa of sulfonylureas
Drug Experimental pKa Calculated pKa % Ionized
Gliclazide 5.8 5.6 97.5
Glimepiride 6.2 5.2 94.1
Glipizide 5.9 5.2 96.9
Glibenclamide 6 5.2 96.2
A charge calculation on each atom was performed on a standard glibenclamide molecule
with both hydrogens deprotonated
24
. The net charge value is shown in Table 3-6. N1 had an
average net charge of -1.041, and N2 had an average net charge of -0.646. The results suggested
that N1 had a larger electronegativity than N2, so it should be easier to deprotonate. Therefore,
glibenclamide with a deprotonated N1 was hypothesized to have a lower average binding score
with or without solvation.
Table 3-6. Charge on N1 and N2 when both hydrogens were deprotonated
Charge Position
Pose N1 N2
1 -1.033 -0.638
2 -1.039 -0.641
3 -1.06 -0.654
4 -1.011 -0.646
5 -1.066 -0.651
Average -1.041 -0.646
3.4.1 Deprotonation on N1
The standard glibenclamide was deprotonated on N1, and 60 poses were generated by
AutoDock Vina, All the poses were solvated by Solvate_GUI (Table 3-7). Compared with the
unprotonated trial, there was no pose in Group 4 after N1 protonation. Before running solvation,
the average ΔG of all 60 poses was -18.2 kcal/mole. Group 2 was the highest affinity group, and
31
ΔG was -9.1 kcal/mol. The average RMSD compared to the N1 unprotonated standard structure
was 3.8. The free energy of Group 3 and Group 1 were -8.8 kcal/mol and -8.6 kcal/mol,
respectively. Group 3 had the lowest RMSD of 3.1. The structure of Group 1 poses were very
different from the standard structure, and the RMSD was 10.1. After solvation, the N1
protonated standard structure had a ΔG of -23 kcal/mol. Group 3 was the group with the highest
affinity to the binding site. It has an average ΔG of -24.4 kcal/mol, which was very close to the
ΔG of the standard structure. The free energy of Group2 was 5.6 kcal/mol higher than that of
Group 3. Group 1 still had poses with low affinity, with ΔG -14.2 kcal/mol.
Table 3-7. Free energy and ΔG of N1 deprotonated glibenclamide
Group Number Average RMSD
ΔG without
solvation (kcal/mol)
ΔG with solvation
(kcal/mol)
1 26 10.1 -8.6 -14.2
2 19 3.8 -9.1* -18.8*
3 15 3.1 -8.8* -24.4*
Total 60 6.3 -8.8 -18.2
Standard -23
Figure 3-5 shows the properties of each pose. Poses in Group 1 mainly accumulated in
the first quadrant, and just a few poses were in the fourth quadrant, which means that they were
very different from the standard structure and the binding affinity was relatively low. Group 2
and Group3 were both in the left part of the plot. Group 2 distributed equally in the second and
third quadrants, but almost all the poses in Group 3 were in the third quadrant. A totally of 14
poses had a ΔG lower than the standard structure, and 7 of these were from Group 3, which
including the top 4 poses with the most negative free energy.
32
Figure 3-5. RMSD vs. ΔG plot for three groups and the standard structure. Poses from Group 1,
2, 3 and the crystal structure were shown in red, yellow, green and purple, respectively. The
horizontal and vertical blue line represent the average ΔG and RMSD, which are -18.2 kcal/mol
and 6.3, respectively.
3.4.2 Deprotonation on N2
In the condition that N2 was deprotonated (Table 3-8), most poses were located in the
middle of the binding site. The average ΔG before solvation was -8.8 kcal/mole. Group 2 had the
lowest ΔG, which was -9 kcal/mol, followed by Group 3, which was -8.8 kcal/mol. The 0.2
kcal/mole gap was not statistically different according to the t-test. Group 4 and 1 had a slightly
lower ΔG of -8.6 kcal/mol and -8.5 kcal/mol respectively, but the gap between group 3 and
group 4 was significant. After solvation, the overall average ΔG was -18.1 kcal/mol, and it was a
little higher than the standard structure, which was -21.2 kcal/mol. Group 3 had the lowest
calculated ΔG, which was -24.6 kcal/mol. Group 1 boosted from the last to the second as a -18.1
33
kcal/mol ΔG. The free energy of Group 2 was -16.9 kcal/mol, and Group 4 had the lowest
binding affinity at -7.8 kcal/mol.
Table 3-8. Free energy and ΔG of N2 deprotonated glibenclamide
Group Number Average RMSD
ΔG without
solvation
(kcal/mol)
ΔG with solvation
(kcal/mol)
1 16 5.2 -8.8 -18.1
2 26 5.2 -8.8 -16.9
3 13 6.5 -8.8 -24.6
4 5 5.0 -8.6 -7.8
Total 60 5.5 -8.8 -18.1
Standard -21.2
Figure 3-6 plotted every pose in the trial. All the poses in Group 1 had a big
conformational difference with the standard structure, but their free energy was widely dispersed
from -6.4 kcal/mol to -23.4 kcal/mol. All the poses in Group 2 had a RMSD lower than 4.24, and
the binding score ranged broadly from -4.4 kcal/mole to -28.2 kcal/mol. Group 3 was considered
to be the best group, since it had a low average RMSD and a low average binding energy. The
number of poses in Group 4 was the fewest among all the groups, and it also had a worse binding
affinity.
34
Figure 3-6. RMSD vs. ΔG plot for four groups and the standard structure. Poses from Groups 1,
2, 3, 4 and the crystal structure are shown in red, yellow, green, blue and purple, respectively.
The horizontal and vertical blue line represent the average ΔG and RMSD, which are -18.1
kcal/mol and 5.3 respectively.
3.4.3 Standard Structure with Protonation on N1 and N2
In order to directly compare the ΔG of the same conformation with different deprotonation
site, the poses in the N2 deprotonation trial were modified. The hydrogen atom on N1 was
deleted, and a hydrogen was added on the deprotonated N2. Poses in the edited trial were in the
exact same conformation with poses in N2 trial, except for the position of deprotonation. The
edited posed were solvated by Solvate_GUI.
35
Table 3-9. Free energy of four trials before solvation
Trial Average ΔG (kcal/mol) Maximum ΔG (kcal/mol) Minimum ΔG (kcal/mol)
Standard -8.9 -8.5 -9.4
N1 -8.8 -8.2 -9.4
N2 -8.8 -8.2 -9.4
Edited -8.8 -8.2 -9.4
Standard was the poses generated by intact standard structure. N1 and N2 were the poses from
N1 and N2 deprotonated standard structure respectively. Edited was the poses edited N2 poses.
In Table 3-9, ΔG before solvation was compared. The four trials were basically similar.
The standard trial from intact standard structure had a 0.1 kcal/mol advantage over the average
ΔG against other trials. Its worst affinity pose was -8.5 kcal/mol, which is better than other trials.
The minimum Δ of all four trials were -9.4 kcal/mol. For ΔG after solvation, the standard trial
was the worst binding trial. The average, maximum and minimum ΔG were all the highest
among four trials, which confirmed that glibenclamide preferred to be protonated in the
physiological environment. Glibenclamide with N1 protonated had a 0.1 kcal/mol higher average
ΔG than N2, and edited N2 structures had the highest average ΔG of -17.6 kcal/mol. However, a
t-test indicated that there was no significant difference with the results for the other three trials.
Therefore, a conclusion cannot be drawn.
Table 3-10. Free energy of four trials after solvation.
Trial
Average ΔG
(kcal/mol)
Maximum ΔG
(kcal/mol)
Minimum ΔG
(kcal/mol)
Standard -13.9 8 -27.2
N1 -18.2 -1.8 -36.2
N2 -18.1 2.6 -31.2
Edited -17.6* -1.4 -29.2
36
4 Chapter 4 – Other Sulfonylureas
In Chapter 4, sulfonylureas other than glibenclamide were assessed. The standard structure
of each molecule was built based on the fully protonated standard structure of glibenclamide.
Fifty docking poses of each molecule were generated by AutoDock Vina, and all the poses were
solvated using Solvated_GUI. They were assumed to bind to SUR1 receptor in the same binding
site as glibenclamide because only one sulfonylurea binding site is observed in the crystal
structure. Poses were grouped based on the position and conformation. The purpose is to explore
the similarities and differences of binding patterns between different sulfonylureas and compare
the binding affinity of sulfonylureas on SUR1.
Glipizide and glimepiride are very similar to glibenclamide. They not only sharing the
same phenylsulfonylurea group, but also have a similar size and structure to glibenclamide.
Therefore, Poses in Group 3 was hypothesized to have the most negative binding energy in
glipizide and glimepiride trials. Gliclazide is the smallest molecule among these four molecules,
so it could have a slightly different binding pattern. The hypothesis was that poses with the most
negative ΔG was not from Group 3.
4.1 Glipizide
A total of 50 docking poses of glipizide were generated by molecular docking. Data for
each group and the standard structure are shown in Table 4-1 and an example of each group is
shown in Figure 4-1. Group 2 and 3 took one third of the total poses. They were in the middle of
the binding site, which was determined by the docking of glibenclamide. The sulfonylurea group
of poses in Group 2 and Group 3 were same between glibenclamide and glipizide. Group 1 was
out of the binding site of glibenclamide, which was about half of total poses. They were all in an
37
unclosed cyclized conformation and located at the closing end of the binding site. Group 4 had
the poses still in the binding site, but in a reversed conformation comparing to the standard
structure. The sulfonylurea group was at the closing end of the binding site rather than the
opening end. Group 3 had the lowest average RMSD because the standard structure was in that
group. Group 2 had a slightly larger average RMSD because it was also located in the middle of
the binding pocket. Both Group 1 and 4 had a large average structural and positional difference
with the standard structure.
Table 4-1. Average RMSD and ΔG for the four groups of glipizide.
Group Number Average RMSD
ΔG without solvation
(kcal/mol)
ΔG with solvation
(kcal/mol)
1 21 9.242 -8.8* -11.2
2 9 3.382 -8.8 -15.9*
3 8 1.766 -9.0* -17.0
4 12 11.418 -8.6 -6.4
Total 50 7.513 -8.8 -11.8
Standard -25.2
38
Figure 4-1. Four groups for glipizide. The image were edited using Chimera 1.14
6
.
Energetically, Group 3 had the lowest average ΔG before and after solvation, which were -
9.0 and -17.0 kcal/mol, respectively. Group 1 and Group 2 had an exact same ΔG before
solvation, which was -8.8 kcal/mol. However, Group 2 had a higher binding affinity than Group
1 after solvation. Group 4 was the Group with the lowest binding affinity before and after
solvation.
A plot including the RMSD and solvated ΔG data of all the poses is shown in Figure 4-2.
The standard structure had a ΔG of -25.2 kcal/mol, which is the second lowest among all the
poses. All the poses in Group 3 was in the third quadrant, which had both a low RMSD and a
low ΔG. Poses in Group 2 concentrated in the third quadrant but two of them had a high binding
energy. Poses in Group 1 and 4 accumulated in the first and fourth quadrants. They both had a
large RMSD compared to the standard structure. However, surprisingly, Group 1 had the top
39
three lowest energy among all the poses, which were poses 50, 30 and 17. Their solvated ΔG
were -26, -22 and -20.4 kcal/mol, respectively.
Figure 4-2. RMSD vs. ΔG plot for four groups and the standard structure. Poses from Groups 1,
2, 3, 4 and the crystal structure were showed in red, yellow, green, blue and purple, respectively.
The horizontal and vertical blue lines represent the average ΔG and RMSD, which are -11.8
kcal/mol and 7.513, respectively.
A plot of pre-solvated and post-solvated ΔG is shown in Figure 4-3. Pose 1, 11, 21, 31 had
the lowest pre-solvated ΔG, and Pose 50, 30 and 17 had the lowest post-solvation ΔG. All of
these poses were from Group 1, so Group 1 had the lowest individual ΔG before and after
solvation. However, these poses were all the second and fourth quadrants, which means that the
poses with a low pre-solvated ΔG had a high post-solvated ΔG, and poses with a low post-
40
solvated ΔG had a high pre-solvated ΔG. Conversely, most poses in Group 3 were in the third
quadrant or on the axis, which means they had a good ΔG both before and after solvation.
In conclusion, poses in Group 3 had the best average score, but Group 1 had the best
individuals from the aspect of energy. Therefore, a conclusion cannot be drawn.
Figure 4-3. Pre-solvated ΔG vs. post-solvated Δ G for each pose. Poses from Group 1, 2, 3 and 4
were shown in red, yellow, green and blue, respectively. The horizontal and vertical blue lines
represented the average ΔG before and after solvation, which are -11.8 and -8.8 kcal/mol,
respectively.
4.2 Glimepiride
Fifty poses were distributed in groups (Table 4-2). Group 3 had poses with the lowest
average free energy before and after solvation, which were -9 and -18.6 kcal/mol, respectively.
Half of total poses were in Group 1. These poses were in an unclosed cyclic form and located at
41
the closing end of the binding site. They have a second lowest average energy before and after
solvation, which were -8.6 and -8.8, respectively. Poses in Group 2 and 4 had the worst binding
affinity to the SUR1. There were not any statistically difference on ΔG between Group 2 and 4
before and after solvation.
Table 4-2. Average RMSD and ΔG for each group.
Group Number Average RMSD
ΔG without
solvation
(kcal/mol)
ΔG with solvation
(kcal/mol)
1 24 10.141 -8.6* -8.8
2 4 6.404 -8.1 -7.9
3 10 1.470 -9.0* -18.6*
4 12 11.922 -8.3 -6.2
Total 50 8.535 -8.5 -10.1
Standard -21
Figure 4-4 shows the post-solvation energy and RMSD of every pose. Group 3 had 6 of top
7 poses, including two of the best. They were Pose 13, 3, 42, 23, 41 and 33. Pose 47 from Group
1 had the third highest energy, which was -20.6 kcal/mol.
Group 3 had both the highest average binding affinity and the lowest individual ΔG.
Therefore, it was considered to be the pattern best representative the binding of glimepiride to
SUR1 receptor. The result confirmed with the hypothesis.
42
Figure 4-4. RMSD vs. ΔG plot for four groups and the standard structure. Poses from Groups 1,
2, 3, 4 and the crystal structure are shown in red, green, yellow, blue and purple, respectively.
The horizontal and vertical blue lines represent the average ΔG and RMSD, which are -10.1
kcal/mol and 8.535, respectively.
4.3 Gliclazide
Fifty poses of gliclazide were generated from the standard structure developed from the
standard glibenclamide. The solvated ΔG of gliclazide standard structure was too poor, which
was 7.8 kcal/mol. The structure was not representative for the trial, and none of the poses was
closely similar to it, including poses in Group 3 (Figure 4-5). The RMSD values of poses in
Group 3 compared to the standard structure were very high. In order to avoid the problem that
the average RMSD of every group was similar, RMSD was calculated relevant to the lowest
energy poses which pose 8 in Group 4.
43
Figure 4-5. All five poses in Group 3 and the standard structure. Colored structures are the
overlapped poses in Group 3, and the gray structure is the standard structure edited from the
glibenclamide. The table shows the RMSD of every pose compared to the standard structure.
The average RMSD and ΔG are shown in Table 4-3. Only five poses were in Group 3, but
Group 3 was still the group with the highest average ΔG before and after solvation. The energy
were -7.6 and -13.5 kcal/mol, respectively. More than half of poses were in Group 4, and it had
the second lowest average ΔG after solvation, which was -10 kcal/mol. Group 2 had a good pre-
solvation ΔG, but the post-solvation Δ G was high. Group 1 had the highest ΔG before solvation
and the second highest post-solvation score.
44
Table 4-3. Average RMSD and ΔG for each group.
Group Number
Average RMSD to
the Best Pose
ΔG without
solvation
(kcal/mol)
ΔG with solvation
(kcal/mol)
1 7 8.414 -7.2 -5.8
2 11 8.468 -7.6 -5.3
3 5 8.450 -7.6 -13.5*
4 27 2.766 -7.5* -10.0*
Total 50 5.375 -7.5 -8.8
Standard 7.8
A plot of RMSD and ΔG is shown in Figure 4-6. There were clearly two clusters. The first
cluster was for poses in Group 4, and the second one was for poses in Group 1, 2 and 3. Group 4
had all top 6 lowest ΔG, which were Pose 8, 28, 38, 46, 18 and 6. Their structures are shown in
Figure 4-7. All of these poses were in a reverse direction comparing to the standard structure, but
their sulfonylurea groups were still in the middle of binding site. Pose 38 was the only pose with
a different conformation in these poses, and it was the third best poses among all the 50 poses.
Moreover, poses in Group 3 also had a good ΔG. Three of them were in top 10, which were Pose
43, 24 and 34.
45
Figure 4-6. RMSD vs. ΔG plot for four groups. Poses from Groups 1, 2, 3, 4 and the crystal
structure are shown in red, green, yellow and blue, respectively. The horizontal and vertical blue
lines represent the average ΔG and RMSD, which were -8.8 kcal and -7.5, respectively.
Figure 4-7. The top 6 poses of gliclazide in SUR1. The green structure was Pose 38, and the
overlapped structures were Pose 8, 28, 46, 18, and 6.
46
A plot of ΔG before and after solvation is shown in Figure 4-8. The poses with a low post-
solvation ΔG accumulated in the fourth quadrant, which means that their pre-solvation energy
was high. Four of five poses in Group 3 were in the third quadrant, which had both a good pre-
solvation ΔG and a good post-solvation ΔG.
Group 3 was the group with the best average ΔG, and Group 4 had the best individual
poses. Therefore, a conclusion cannot be drawn.
Figure 4-8. Pre-solvated ΔG vs. post-solvated Δ G for each pose. Poses from Group 1, 2, 3 and 4
are shown in red, yellow, green and blue, respectively. The horizontal and vertical blue lines
represent the average ΔG before and after solvation, which are – 7.5 and -8.8 kcal/mol,
respectively.
47
5 Chapter 5 - Discussions
5.1 Binding of Glibenclamide
The binding pattern of glibenclamide and SUR1 consisted of two aspects. The first one
was the structure and conformation of the ligand, and the second one was the position of the
ligand.
Structurally, molecular docking suggested that the cis-glibenclamide was more
energetically preferable. The results agreed with the conclusion of Matsumura et al.
14
, Bryantsev
et al.
13
and the crystal structure from X-ray crystallography
23
. For deciding the deprotonation
site, molecular docking did not provide a statistically significant result from the aspect of free
energy. However, the study of Kamp et al.
28
indicated that the protonation site was on N1.
Actually, in the molecular docking of N1 deprotonation and N2 deprotonation trials, the lowest
energy among all the poses were Pose 36 from the N1 deprotonation trial. Therefore, data from
Kamp et al. were considered reliable. However, since molecular docking could not detect the
minor effects on deprotonation site, it was still appropriate to use a standard cis-glibenclamide
without deprotonation.
The ΔG data before and after solvation suggested different groups as the most likely
binding positions. The pre-solvation ΔG preferred Group 2, and the post-solvation ΔG picked
Group 3. The crystal structure of glibenclamide and SUR1 provided a standard answer that
glibenclamide bound with SUR1 as the pattern of Group 3. Therefore, the post-solvation ΔG
provided a more reliable evidence for the most possible pattern.
48
Figure 5-1. Binding of Pose 36 without water molecules.
Pose 16 from the standard trial was used to discover the binding pattern of glibenclamide.
Pose 16 was an example of Group 3 (Figure 5-1). There were three direct connections between
glibenclamide and SUR1 receptor. Arg1246 and Thr1242 were the key amino acid to form
hydrogen bonds. Two guanidine hydrogens on arginine interacted with the same sulfonyl oxygen
and formed two hydrogen bonds. Moreover, the hydrogen on the hydroxyl group of threonine
connected to the urea oxygen on glibenclamide.
49
Figure 5-2. Binding of Pose 36 with water molecules.
Figure 5-2 shows the binding pattern of glibenclamide with water molecules. All the
residues, which connected to glibenclamide in less than 5 water-bridge connections, are shown in
the figure. There were totally 9 residues connected with the ligand through water bridges. They
were Trp430, Val587, Thr588, Gln1190, Asp1193, Ala1237, Thr1242, Arg1246 and Asp1304.
These residues surrounded the ligand from all the orientations and fixed the ligand in the binding
site.
5.2 Binding of Glipizide
The molecular docking of glipizide narrowed the possible binding pattern to two
possibilities. The first one was to bind with the receptor in the same manner as glibenclamide
and formed direct connections with Arg1246 and Thr1242. The second one was to bind in Group
50
1 conformation, which was located at the opening end of the binding site in an unclosed cyclic
form.
Figure 5-3. Binding of Pose 50 without water molecules.
Pose 50 from Group 1 had the lowest post-solvation ΔG, so it was analyzed. There were
only 2 connections between gliclazide and SUR1 (Figure 5-3). Two hydrogens on Arg306
formed two hydrogen bonds with the same nitrogen on the pyrazine of glipizide. The connection
was weaker than Group 3 pattern, which had three connection with two residues.
After adding water molecules, cyclic glipizide formed connection with 8 residues in less
than 5 water bridges (Figure 5-4). They were Arg360, Gln369, Trp430, Asn437, Ile585,
Arg1246, Arg1300 and ASN1301. Residue surrounded ligand and fixed the ligand in the site.
Glipizide shared Trp430 and Arg1246 with solvated glibenclamide.
51
Figure 5-4. Binding of Pose 50 with water molecules.
5.3 Binding pattern of Glimepiride
The result of molecular docking strongly suggested that glimepiride bound with SUR1 in
the form of Group 3. Pose 13 was selected to be the example of binding pattern analyzing. Pose
13 connected to the receptor very similar to glibenclamide without water (Figure 5-5). It formed
three hydrogen bonds with Arg1246 and Thr1242. However, unlike glibenclamide, there was
52
only one hydrogen bond between Arginine and glimepiride, and 2 hydrogen bonds were formed
between threonine and the ligand.
Figure 5-5. Binding of Pose 13 without water molecules.
The solvated glimepiride had fewer connection with SUR1 comparing to solvated
glibenclamide (Figure 5-6). A total of 5 residues connected with glimepiride in less than 5 water
bridges. The key residues were Trp430, Asn437, Gln1190, Thr1242 and Arg1246. All these
residues were crucial in glibenclamide binding pattern, except Asn437.
53
Figure 5-6. Binding of Pose 13 with water molecules.
5.4 Binding pattern of Gliclazide
Gliclazide was the smallest ligand being studied, and it was also the only sulfonylurea
which preferred to bind in a reverse orientation. Pose 8 was the pose with the best solvated ΔG,
so this structure was used for studied the binding pattern.
Pose 8 only connected to Thr1242 in one hydrogen bond, which is the fewest among all
the molecules (Figure 5-7). It confirmed with the result that gliclazide had the highest pre-
solvation binding energy among four molecules.
54
Figure 5-7. Binding of Pose 8 without water molecules.
Figure 5-8. Binding of Pose 8 with water molecules.
55
The solvated gliclazide connected with 8 residues, which was the second most among 4
molecules (Figure 5-8). The key residues were Gln374, Asn426, Trp430, Gln1190, Thr1242,
Arg1246 and Asp1304. The significant residues for four molecules were shown in Figure 5-9.
The commonly shared significant residues were Trp430 and Arg1246.
Figure 5-9. Significant residues for each molecule and shared residues among four molecules.
5.5 Ranking of Sulfonylureas Activities
In research by Abdelmoneim et al., the IC50 of four molecules were ranked in the sequence
of glibenclamide, glimepiride, glipizide and gliclazide from the lowest to the highest, and the
binding affinity of glimepiride and glipizide were basically same
22
. Molecular docking calculated
56
the free energy of four molecules. If the rank was coincident with the experimental data,
molecular docking was considered successfully predicting the binding pattern.
There were multiple indices of ΔG value from molecular docking. All of them are listed in
Table 5-1. Firstly, the average overall ΔG was the average free energy of all the poses. The rank
of ΔG from the lowest to the highest was glibenclamide, glipizide, glimepiride, and gliclazide.
The rank basically agreed with the experimental data, except the order of glimepiride and
glipizide. However, the difference between the experimental ΔG of two molecules was very
small, so the error could be ignored.
Table 5-1. Free energy of four sulfonylureas.
Drug Average overall ΔG
(kcal/mol)
Average ΔG of the
best Group (kcal/mol)
Lowest ΔG
(kcal/mol)
Gliclazide -8.8 -13.5 -24.8
Glimepiride -10.1 -18.6 -21.4
Glipizide -11.8 -17 -26
Glibenclamide -13.9 -19.7 -27.2
Although all of four molecules had four groups of conformation, only the best group
represented the actual binding affinity of the molecule. Therefore, in order to rank the affinity of
four sulfonylureas in the physiological environment, average ΔG of the groups, which has the
lowest average ΔG, were compared. They were Group 1 of gliclazide, Group 3 for glimepiride,
Group 4 of glipizide and Group 3 of glibenclamide. The rank was in the order of glibenclamide,
glimepiride, glipizide, and gliclazide. The order was exactly the same as the reference data.
57
The lowest energy poses represented the best condition of binding among all the docking
poses. It was considered best representing the binding pattern in the physiological environment if
all the possible conformation were searched. Pose 36 of glibenclamide, Pose 50 of glipizide,
Pose 13 of glimepiride and Pose 8 of gliclazide were compared. The result was not as well as
average ΔG comparison. The rank was in the order of glibenclamide, glipizide, gliclazide and
glimepiride. It was not same as the experimental data. The error could be due to an insufficient
amount of data. As mention in Section 1.1, AutoDock Vina used a random search algorithm. A
sufficient number of trials were necessary for generating all the possible conformations. In this
study, only 50 poses of glimepiride were generated, which was not enough.
In general, molecular docking greatly rank the binding affinity of four sulfonylureas, but a
larger size of data could improve the result.
5.6 Limitation of the study and further research
The study generally reached the desired goal, which was to assess the most favorable
conformation of sulfonylureas in the complex, discover the binding pattern of SUR1-ligand
complexes and exploring the mechanism of energy calculation in molecular docking. However,
there were still some points to be improved.
Firstly, an approximate range of binding site for all the sulfonylureas was determined by the
position of the standard structure of glibenclamide. The decision was made under the assumption
that all the sulfonylureas bound with SUR1 in a same pattern. However, the results indicated
that, sulfonylureas did not bind same. Therefore, range of molecular docking search box was not
accurate. In order to improve the performance, a much large search box should be used.
58
Secondly, the energy calculation of Solvate_GUI was using a different parameter from
AutoDock Vina, so the pre-solvation and post-solvation ΔG cannot be compared directly. If a
same parameter could be used, it could be possible to discover the effect of solvation on free
energy. Sulfonylureas were hydrophilic molecules, and if a hydrophobic molecule was tested the
result could be opposite. This could be the next step of the study.
Lastly, the result of molecular docking did not give a conclusion on the protonation site of
sulfonylureas, but N1 deprotonations trial had the slightly higher average ΔG and the best
individual ΔG. If more poses were generated, it would be possible to draw a conclusion.
Therefore, a much bigger date size should be created in the future.
59
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62
Appendix
Appendix A: Standard glibenclamide
Group
ID
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/mol)
Calc Delta-G (kcal/mol
2 1 368 424 394 4 5 13 8 3 6 8 7 3 334 55 1 0 0 0 3.439
-9.3 -17.6
2 2 360 431 399 5 6 13 7 3 4 8 2 4 352 51 1 0 0 0 3.692
-9 -15
3 3 304 407 395 5 2 15 5 4 7 5 3 6 339 38 2 0 0 0 2.951
-9 -19.2
3 4 397 421 385 6 4 16 7 3 5 8 3 2 346 47 2 0 0 0 3.144
-9 -17.6
3 5 332 419 394 5 3 15 7 5 6 6 3 2 336 54 1 0 0 0 2.858
-9 -21.6
3 6 353 420 401 5 0 20 11 2 6 4 1 2 337 57 2 0 0 0 2.803
-8.8 -20.8
1 7 355 380 360 2 4 15 1 1 6 12 9 5 299 47 2 0 0 1 9.284
-8.7 5
4 8 390 444 427 2 1 13 7 1 7 8 9 4 351 57 2 0 0 0 5.32
-8.6 -7.6
2 9 337 428 392 3 2 15 6 4 7 7 2 3 353 46 1 0 0 0 3.133
-8.6 -17.4
1 10 387 439 416 3 6 13 3 0 8 7 8 5 354 54 2 0 0 0 11.165
-8.6 -3
2 11 359 429 397 5 5 12 7 4 6 7 4 4 349 48 1 0 0 0 3.704
-9.1 -21
2 12 375 429 404 4 5 13 7 4 5 9 3 2 344 55 0 0 0 1 4.156
-9 -15.8
3 13 280 408 382 5 2 14 5 5 6 5 3 6 328 50 1 0 0 0 3.221
-8.9 -18.8
3 14 298 415 391 5 3 12 5 6 8 7 3 7 331 48 0 0 0 0 3.031
-8.9 -26.6
1 15 334 369 355 5 4 14 6 2 5 9 9 3 296 39 1 0 0 1 8.964
-8.8 -13.6
3 16 321 432 403 8 3 16 8 3 7 8 3 1 346 56 1 0 0 0 3.427
-8.7 -27.2
3 17 283 414 383 6 1 15 9 1 4 8 3 3 328 58 1 0 0 1 3.57
-8.7 -13.6
63
4 18 311 426 402 3 1 16 6 5 5 9 1 3 343 54 0 0 0 0 3.111
-8.6 -16
4 19 359 427 414 4 5 15 8 4 3 6 6 3 359 38 4 0 0 0 3.828
-8.5 -11.4
1 20 388 441 416 3 5 13 5 0 5 5 9 7 355 55 1 0 0 1 11.338
-8.5 -1
2 21 346 430 398 5 4 14 7 4 7 8 3 3 350 48 1 0 0 0 3.722
-9.3 -22.8
2 22 350 407 387 4 4 14 6 3 8 8 6 3 339 34 2 0 0 0 3.924
-9.1 -19.8
3 23 300 408 389 5 2 11 6 5 6 4 3 5 333 46 1 0 0 0 3.012
-9 -21.4
3 24 304 416 398 5 3 12 5 6 7 7 3 4 335 49 0 0 0 0 3.031
-8.9 -24.6
1 25 316 386 370 7 1 17 4 3 2 9 8 2 309 49 1 0 0 0 9.574
-8.9 -10.4
1 26 347 396 367 4 2 18 6 1 6 7 8 3 301 64 2 0 0 0 12.857
-8.8 -6.6
1 27 333 371 353 5 3 12 7 0 5 7 10 2 291 49 2 0 0 1 9.011
-8.7 -7.8
1 28 317 370 345 3 1 19 7 2 4 12 4 3 296 41 2 0 0 0 11.783
-8.6 -9.2
1 29 329 378 355 2 3 16 1 0 5 11 10 4 293 54 2 0 0 0 9.318
-8.6 8
1 30 293 387 364 5 0 15 5 1 4 5 8 3 308 53 0 0 0 0 7.802
-8.6 -9.4
2 31 352 431 400 5 4 14 7 3 5 10 2 4 347 53 1 0 0 0 3.722
-9.3 -16.4
2 32 367 430 411 4 6 12 7 4 4 9 4 2 354 46 1 0 0 1 4.176
-9.1 -13.8
3 33 285 409 391 5 2 12 5 4 7 6 2 5 341 39 1 0 0 0 3.212
-8.9 -21
3 34 338 413 386 7 2 17 6 1 4 7 4 3 338 50 2 0 0 0 3.832
-8.9 -11.8
1 35 317 373 345 3 2 18 8 3 5 9 8 3 293 44 1 0 0 0 12.075
-8.8 -16
1 36 270 369 341 2 4 13 3 1 7 8 5 7 290 48 1 0 0 2 8.473
-8.7 -0.2
3 37 321 421 397 5 3 15 8 6 6 3 4 3 339 52 2 0 0 0 2.838
-8.6 -23.6
1 38 346 376 364 3 4 14 4 1 5 8 9 3 303 43 4 0 0 0 9.722
-8.6 0.6
1 39 354 425 398 4 0 11 7 2 7 10 4 2 337 56 0 0 0 0 10.019
-8.6 -17.6
1 40 348 416 374 4 3 10 6 3 6 7 6 5 326 57 0 0 0 1 10.363
-8.5 -13.6
2 41 364 423 402 4 5 14 8 4 5 6 6 3 347 44 1 0 0 1 3.448
-9.4 -17.8
2 42 342 430 392 4 5 18 7 5 5 8 2 5 341 57 3 0 0 0 3.729
-9.4 -13.2
3 43 344 411 390 4 5 15 5 3 7 7 4 4 329 52 2 0 0 0 3.794
-9.2 -12.6
2 44 374 424 396 5 3 14 9 4 4 9 2 2 337 57 2 0 0 0 3.097
-9.2 -17.2
2 45 264 408 380 5 3 12 6 4 5 5 5 8 334 41 0 0 0 0 3.278
-9.1 -20.8
3 46 329 400 378 7 1 14 4 4 6 7 4 2 325 48 1 0 0 0 4.508
-9.1 -19.6
3 47 341 371 348 4 3 12 7 1 3 9 6 3 299 43 2 0 0 1 9.027
-9 -5.2
1 48 307 416 396 5 1 10 4 6 7 9 3 7 337 43 2 0 0 0 2.986
-9 -20
1 49 354 422 390 5 2 13 5 2 5 8 6 5 341 50 4 0 0 0 10.408
-8.8 -5.6
4 50 383 440 439 2 1 11 7 0 4 7 7 6 351 58 1 0 0 1 5.339
-8.7 -0.2
64
2 51 365 422 392 4 5 12 9 4 4 10 5 3 339 47 1 0 0 0 3.428
-9.4 -19.2
2 52 351 408 378 4 5 13 6 3 7 8 5 4 330 45 1 0 0 0 3.941
-9.3 -17.8
3 53 282 409 394 5 2 13 5 5 7 5 3 6 336 42 1 0 0 0 3.015
-9.2 -22.2
2 54 342 432 403 4 3 17 6 5 3 8 3 5 353 49 3 0 0 0 3.835
-9.2 -9.4
1 55 324 372 356 5 3 10 5 1 6 8 9 4 297 42 2 0 0 1 8.892
-9.1 -9.2
2 56 378 429 402 4 5 12 8 4 6 8 4 2 351 46 1 0 0 1 4.159
-9.1 -19.2
3 57 346 415 385 6 3 13 8 2 7 8 5 3 331 51 1 0 0 0 3.139
-8.9 -22.4
1 58 384 414 391 5 4 11 6 3 4 7 7 6 333 48 0 0 0 1 10.386
-8.8 -13.8
1 59 347 404 380 4 3 12 5 1 5 8 7 3 311 64 2 0 0 1 9.802
-8.7 -1
2 60 329 409 388 1 0 17 4 4 8 9 5 2 329 48 1 0 0 0 4.918
-8.7 -11.2
65
Appendix B: Glibenclamide with N1 deprotonation
Group
ID
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/ mol)
Calc Delta-G (kcal/ mol
2 1 363 428 389 5 4 16 8 5 6 6 4 2 343 54 0 0 0 0 3.714 -9.3 -25.4
3 2 279 412 387 5 2 14 9 2 8 4 3 6 326 54 2 0 0 0 2.997 -9 -21.4
2 3 326 404 367 7 1 17 6 2 7 9 4 2 323 51 0 0 0 0 4.621 -9 -22.8
2 4 359 420 390 4 3 15 4 3 9 9 5 5 327 58 1 0 0 0 4.01 -8.9 -15.2
1 5 362 399 364 5 1 19 8 3 3 7 6 5 317 50 2 0 0 0 12.889 -8.9 -13.2
2 6 362 442 415 4 2 15 8 3 5 7 6 4 351 58 1 0 0 1 4.179 -8.6 -13.2
1 7 325 398 363 9 1 13 8 1 4 11 5 5 311 53 3 0 0 0 8.901 -8.6 -16.8
1 8 300 387 364 5 1 17 8 6 7 6 5 1 312 42 2 0 0 0 7.772 -8.6 -27.4
3 9 336 428 393 5 2 13 7 6 11 3 1 3 335 62 2 0 0 0 2.932 -8.6 -28.8
1 10 350 434 397 3 1 10 5 2 11 11 2 3 342 58 1 0 0 0 10.007 -8.5 -16.8
2 11 360 424 392 4 5 14 10 2 6 6 6 5 340 49 1 0 0 1 3.571 -9.4 -18.6
2 12 338 429 410 4 5 17 8 3 6 9 3 5 343 52 2 0 0 0 3.856 -9.4 -16.2
2 13 359 408 382 4 4 13 8 3 8 8 5 5 325 46 0 0 0 0 3.907 -9.3 -25
3 14 292 414 394 5 2 13 9 2 8 4 3 7 327 54 2 0 0 0 2.967 -9.1 -21.4
1 15 329 387 359 5 0 16 9 3 4 7 7 5 298 54 2 0 0 0 12.806 -9 -16
1 16 356 427 393 5 2 14 7 2 6 9 6 3 346 48 2 0 0 0 10.454 -8.9 -15.4
1 17 285 365 345 2 4 9 5 0 8 7 7 6 283 49 1 0 0 1 8.413 -8.8 -5.6
3 18 359 424 393 5 0 18 10 5 11 5 4 0 336 53 1 0 0 0 2.55 -8.8 -36.2
1 19 357 418 381 5 3 9 9 3 6 8 6 5 339 42 0 0 0 1 10.392 -8.7 -24
1 20 382 442 406 3 6 11 6 0 4 4 9 7 365 47 1 0 0 1 11.366 -8.7 -2.6
66
2 21 358 432 403 5 4 13 8 4 6 7 2 3 348 54 0 0 0 0 3.717 -9.3 -23.6
2 22 357 423 391 4 4 13 10 2 5 9 4 5 337 51 0 0 0 0 3.473 -9.3 -20.4
3 23 285 413 372 5 1 14 9 2 8 4 4 6 330 50 1 0 0 0 2.973 -9 -24.2
3 24 338 405 386 3 2 19 5 5 6 9 5 3 323 49 0 0 0 0 4.763 -9 -17
3 25 315 420 387 5 3 12 10 4 7 6 1 6 333 53 0 0 0 0 3.045 -8.9 -29.2
3 26 391 423 394 6 4 15 7 3 9 9 3 4 341 47 2 0 0 0 3.434 -8.9 -24.8
1 27 334 386 360 5 1 18 9 2 3 6 7 4 304 51 1 0 0 0 12.838 -8.9 -15
3 28 339 413 380 7 2 15 6 1 10 7 4 6 315 64 2 0 0 0 3.873 -8.9 -19.8
1 29 267 363 343 2 5 8 6 0 7 5 7 7 283 48 2 0 0 2 8.508 -8.8 -1.8
1 30 394 447 415 3 5 11 7 0 7 6 9 5 357 56 2 0 0 1 11.372 -8.6 -6
2 31 369 429 394 5 4 14 7 4 7 7 3 3 347 51 0 0 0 0 3.746 -9.3 -24.2
2 32 334 409 381 6 2 12 5 2 7 12 5 2 311 65 1 0 0 0 3.944 -9 -14.2
3 33 298 413 383 5 2 15 9 3 8 4 4 6 327 52 2 0 0 0 2.969 -9 -23.6
1 34 344 384 365 7 3 15 9 1 4 6 7 5 314 38 2 0 0 0 9.385 -8.9 -19.6
1 35 279 377 349 2 3 11 5 0 9 5 8 3 304 43 1 0 0 2 8.492 -8.8 -6.6
3 36 301 422 403 5 3 17 8 4 7 3 1 3 333 63 2 0 0 0 2.576 -8.7 -19.6
1 37 321 393 367 9 1 15 7 2 5 9 4 4 309 53 2 0 0 0 8.785 -8.6 -20.6
1 38 311 389 364 6 1 15 5 5 4 7 2 3 307 56 1 0 0 0 8.273 -8.5 -16
2 39 315 418 394 2 2 17 7 4 9 6 2 2 339 49 1 0 0 0 3.024 -8.5 -20.2
1 40 345 426 387 3 1 11 5 3 8 10 3 3 338 56 1 0 0 0 9.967 -8.5 -13.6
2 41 341 433 405 4 4 17 10 3 6 8 2 4 353 47 2 0 0 1 3.733 -9.2 -18.8
2 42 361 411 386 4 4 16 6 2 6 9 5 4 336 43 0 0 0 0 3.996 -9.1 -16.6
2 43 354 422 401 4 4 11 10 1 5 8 5 6 337 50 0 0 0 1 3.423 -9.1 -16.8
2 44 388 425 411 3 5 12 6 2 5 8 5 4 343 52 0 0 0 2 4.189 -8.9 -7
3 45 293 414 390 5 2 13 9 2 7 4 3 7 328 54 1 0 0 0 2.987 -8.9 -21.6
1 46 307 373 348 5 4 12 9 2 5 5 6 6 293 47 3 0 0 1 8.946 -8.8 -13.4
1 47 339 389 367 5 1 16 9 2 4 7 8 4 304 51 3 0 0 0 12.814 -8.7 -12.8
1 48 351 426 386 5 2 14 7 2 4 9 6 3 350 45 3 0 0 1 10.449 -8.7 -8.4
1 49 318 383 359 3 4 15 8 2 3 6 8 7 305 44 1 0 0 0 9.754 -8.6 -10.6
3 50 332 422 380 5 1 17 8 9 10 2 0 2 330 61 2 0 0 0 2.829 -8.4 -34.4
2 51 341 433 418 4 5 19 9 4 7 7 2 4 354 46 2 0 0 1 3.749 -9.2 -20.8
2 52 396 429 405 4 3 13 8 3 5 9 5 4 337 58 0 0 0 0 4.138 -9 -17.2
67
3 53 285 414 379 5 2 13 9 3 7 4 3 6 333 49 2 0 0 0 2.977 -8.9 -22.4
3 54 334 425 400 5 2 16 8 4 7 1 3 6 344 52 2 0 0 0 2.841 -8.6 -21.8
1 55 321 387 366 3 5 16 4 1 8 7 7 6 304 50 2 0 0 2 8.998 -8.3 -3.4
1 56 307 411 371 5 2 11 6 3 9 10 5 2 325 51 0 0 0 0 9.618 -8.3 -24.2
1 57 306 430 401 6 1 15 7 4 6 9 3 3 339 59 0 0 0 1 10.901 -8.3 -20.8
2 58 326 423 388 4 4 15 7 3 7 7 3 4 341 51 0 0 0 0 3.172 -8.3 -20.4
1 59 305 418 380 3 3 17 5 3 9 9 3 4 332 53 0 0 0 0 9.571 -8.2 -18
1 60 284 429 401 4 1 15 6 2 10 9 4 4 341 53 0 0 0 0 10.305 -8.2 -21.8
68
Appendix C: Glibenclamide with N2 deprotonation
Group
ID
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/mol)
Calc Delta-G (kcal/mol
2 1 366 431 413 5 5 13 7 4 6 6 3 4 347 54 0 0 0 0 3.607 -9.1 -21.8
2 2 379 426 406 4 3 13 6 1 4 10 4 4 330 67 0 0 0 1 4.242 -9.0 -4.4
3 3 308 414 388 5 2 14 9 2 9 4 4 7 324 55 2 0 0 0 2.972 -8.9 -23
2 4 357 416 375 4 5 14 8 2 5 9 5 5 316 66 2 0 0 0 3.967 -8.9 -9.8
3 5 318 416 388 5 2 13 9 6 9 4 0 3 335 50 2 0 0 0 2.87 -8.5 -31.2
2 6 344 425 405 5 4 15 6 2 7 8 2 4 347 49 0 0 0 0 3.151 -8.5 -19.2
1 7 348 395 377 4 0 19 8 1 6 5 8 4 314 49 1 0 0 0 9.715 -8.4 -15.2
3 8 356 427 395 4 2 13 9 3 8 3 2 3 346 53 0 0 0 0 2.963 -8.3 -25.4
1 9 302 362 339 6 4 11 9 1 7 6 3 7 294 35 0 0 0 0 9.577 -8.2 -27.6
2 10 314 422 391 4 0 12 3 4 9 8 3 4 344 47 1 0 0 0 2.612 -8.2 -17.4
2 11 349 430 397 5 6 11 8 4 6 6 5 3 349 49 0 0 0 0 3.724 -9.1 -24.6
2 12 351 410 381 4 4 14 6 3 8 7 7 3 328 48 0 0 0 0 3.879 -9.1 -21
2 13 375 416 389 4 6 12 8 3 5 7 4 3 322 64 0 0 1 0 3.266 -9.0 -15
3 14 301 413 388 5 2 14 9 3 8 4 4 7 312 66 1 0 0 0 3.028 -8.9 -22.8
1 15 351 427 398 6 3 13 7 1 5 8 6 3 350 47 1 0 0 0 10.314 -8.7 -16
2 16 377 429 397 4 3 11 7 3 4 8 4 4 345 54 0 0 0 0 4.23 -8.7 -14.4
3 17 306 423 398 5 3 17 8 5 7 4 2 5 320 72 1 0 0 1 2.876 -8.7 -19.6
1 18 346 371 345 4 2 16 7 2 7 6 8 6 299 36 3 0 0 1 8.917 -8.6 -13.6
4 19 387 464 440 2 1 13 6 0 6 6 6 5 374 60 1 0 0 0 5.199 -8.5 -3.6
1 20 370 418 378 8 1 15 7 5 3 7 3 4 340 49 2 0 0 1 8.144 -8.4 -19.2
69
2 21 364 430 398 5 5 13 8 3 7 8 4 4 339 57 0 0 0 0 3.619 -9.2 -23
2 22 350 405 377 4 4 14 5 2 6 7 4 6 324 51 2 0 0 0 3.854 -9.1 -9.2
3 23 285 412 386 5 2 13 10 2 9 3 4 7 325 52 1 0 0 0 3.26 -9.0 -27.4
2 24 371 439 409 4 4 13 8 2 5 6 6 3 344 65 0 0 0 1 4.058 -8.9 -12
1 25 345 375 353 4 2 14 9 1 4 6 7 6 303 39 1 0 0 0 8.886 -8.7 -15.4
4 26 382 460 432 2 1 12 5 1 8 7 6 4 372 57 2 0 0 0 5.266 -8.5 -5.8
1 27 347 361 343 1 4 17 9 2 6 8 5 3 287 41 1 0 0 0 10.741 -8.4 -14.4
1 28 303 432 413 5 2 15 6 4 8 7 3 4 338 62 0 0 0 1 10.9 -8.3 -20
1 29 325 428 416 3 2 16 8 1 4 7 5 5 340 58 0 0 0 0 11.054 -8.3 -9.8
1 30 268 362 329 7 2 15 6 3 10 9 4 2 280 48 2 0 0 0 7.095 -8.3 -26.6
2 31 345 429 397 5 5 13 8 5 7 7 3 3 347 49 0 0 0 0 3.753 -9.3 -28.2
3 32 305 413 388 5 2 13 10 3 9 4 3 6 329 49 2 0 0 0 3.069 -9.0 -27.8
2 33 354 409 383 5 2 15 8 2 7 8 6 4 323 51 1 0 0 1 4.06 -9.0 -18.4
2 34 375 430 408 4 7 13 8 1 4 9 3 4 351 50 0 0 0 1 4.086 -8.8 -11.4
2 35 337 427 411 5 4 17 6 3 6 8 3 4 348 49 0 0 0 0 3.318 -8.6 -19.2
3 36 322 420 394 5 2 14 8 4 10 2 1 4 339 52 0 0 0 0 2.707 -8.6 -31.2
1 37 332 399 379 4 0 21 6 2 7 6 7 4 316 51 1 0 0 0 9.687 -8.6 -14.8
4 38 346 461 429 2 2 13 4 2 7 7 6 7 372 56 1 0 0 0 4.955 -8.5 -6.2
2 39 357 411 381 4 3 15 6 1 6 6 6 3 333 50 2 0 0 0 4.03 -8.4 -9.4
1 40 368 434 407 3 2 9 9 3 8 7 4 3 344 56 1 0 0 0 10.673 -8.3 -20.8
2 41 350 423 391 4 5 13 10 2 4 9 5 4 338 51 0 0 0 0 3.554 -9.4 -18.6
2 42 367 432 401 4 5 17 9 4 6 6 2 3 350 52 2 0 0 0 3.84 -9.4 -19.8
2 43 364 412 386 4 5 13 6 2 5 9 5 4 333 48 1 0 0 0 3.979 -9.4 -11.8
2 44 349 426 406 4 3 12 7 2 5 8 4 4 345 51 0 0 0 0 4.222 -9.3 -15
3 45 308 414 391 5 2 14 9 2 7 4 4 7 329 52 1 0 0 0 2.978 -9.2 -22
3 46 346 442 399 4 2 15 8 3 9 5 4 6 336 71 2 0 0 0 4.734 -8.8 -17.8
4 47 399 463 425 2 1 15 6 0 5 6 6 6 372 62 3 0 0 0 5.202 -8.7 2.6
2 48 352 424 402 5 4 14 5 4 8 10 2 4 347 44 0 0 0 0 3.142 -8.7 -23.8
3 49 331 424 387 5 1 16 7 3 11 4 1 5 340 53 2 0 0 0 2.52 -8.7 -25.2
1 50 315 425 389 6 1 16 4 4 11 9 4 3 327 63 1 0 0 0 10.462 -8.7 -23.6
2 51 369 428 401 5 4 12 8 5 5 8 2 3 345 52 0 0 0 0 3.708 -9.3 -24
2 52 343 410 373 4 4 12 6 2 5 8 5 4 326 54 1 0 0 0 3.879 -9.2 -10.6
1 53 330 373 346 5 1 18 8 4 6 13 4 3 292 43 0 0 0 0 11.983 -9.1 -25.8
70
2 54 385 427 392 4 3 13 6 3 6 8 6 4 345 49 0 0 0 1 4.206 -9.1 -15.2
3 55 303 414 395 5 2 15 9 2 7 4 4 6 333 49 2 0 0 0 3.243 -9.0 -20.6
1 56 372 402 375 4 1 21 8 3 4 5 6 7 305 64 3 0 0 0 12.661 -8.9 -8.2
3 57 332 425 405 5 3 14 8 4 8 4 1 4 344 52 1 0 0 0 2.572 -8.8 -25.6
4 58 363 434 406 4 1 9 5 3 12 11 3 3 347 50 0 0 0 0 10.095 -8.7 -26
2 59 347 426 387 5 4 15 5 3 9 8 2 4 341 54 0 0 0 0 3.147 -8.6 -21.8
1 60 382 417 383 6 3 11 9 3 4 6 6 3 331 55 0 0 0 2 10.401 -8.6 -17.8
71
Appendix D: Edited N2 deprotonated glibenclamide
Group
ID
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/ mol)
Calc Delta-G (kcal/ mol
2 1 347 432 393 5 5 12 7 3 8 7 5 5 339 58 0 0 0 0 3.607 -9.1 -22.8
2 2 369 427 414 4 3 13 6 4 5 10 5 4 341 52 0 0 0 1 4.242 -9 -14.6
3 3 287 414 384 5 2 13 9 3 8 4 3 7 327 53 2 0 0 0 2.972 -8.9 -23.4
2 4 349 416 387 4 5 13 8 2 4 8 5 5 335 49 1 0 0 1 3.967 -8.9 -11.4
3 5 303 417 388 5 2 15 9 6 7 3 1 3 331 57 1 0 0 0 2.87 -8.5 -28.2
2 6 336 426 399 5 4 15 6 2 8 8 3 4 356 39 0 0 0 0 3.151 -8.5 -23
1 7 325 396 373 3 0 18 8 1 6 6 7 4 306 58 1 0 0 1 9.715 -8.4 -9.4
3 8 343 427 391 4 2 14 9 4 9 3 2 2 331 67 0 0 0 0 2.963 -8.3 -26.2
1 9 302 364 332 6 4 10 9 1 7 7 2 6 286 46 1 0 0 0 9.577 -8.2 -23.4
2 10 322 422 387 4 0 13 3 2 11 7 2 4 340 53 1 0 0 0 2.612 -8.2 -16.2
2 11 347 430 403 5 6 12 8 2 8 6 4 4 347 51 0 0 0 0 3.724 -9.1 -24.2
2 12 363 410 386 4 4 14 6 2 8 9 6 3 331 45 0 0 0 0 3.879 -9.1 -19.8
2 13 362 417 392 4 6 13 8 3 6 6 5 3 323 63 0 0 1 0 3.266 -9 -17
3 14 287 413 390 5 2 13 9 2 7 4 3 7 325 56 1 0 0 0 3.028 -8.9 -21.2
1 15 348 428 386 5 3 13 7 2 5 9 6 2 341 56 3 0 0 1 10.314 -8.7 -8
2 16 358 429 398 4 3 12 7 3 5 9 3 4 350 48 0 0 0 1 4.23 -8.7 -15.4
3 17 316 423 401 5 3 17 8 3 6 4 1 4 337 60 2 0 0 0 2.876 -8.7 -16.6
1 18 308 371 348 5 2 14 7 2 8 5 7 6 307 29 4 0 0 1 8.917 -8.6 -16.8
4 19 383 465 431 2 1 12 6 0 6 7 6 6 368 65 1 0 0 0 5.199 -8.5 -2.6
1 20 353 418 378 7 1 15 7 4 3 7 3 3 349 42 2 0 0 1 8.144 -8.4 -16.8
72
2 21 353 430 402 5 5 13 8 3 7 8 4 4 337 59 0 0 0 0 3.619 -9.2 -22.6
2 22 355 406 386 4 4 13 5 2 5 8 5 5 326 50 2 0 0 0 3.854 -9.1 -7.6
3 23 275 412 395 5 2 12 10 2 8 3 3 6 335 45 1 0 0 0 3.26 -9 -27
2 24 356 439 407 4 4 13 8 1 7 6 5 3 349 60 0 0 0 1 4.058 -8.9 -14.8
1 25 327 375 345 5 2 12 9 1 4 6 7 6 291 51 2 0 0 1 8.886 -8.7 -11
4 26 385 461 435 2 1 13 5 1 7 8 8 6 359 67 1 0 0 0 5.266 -8.5 -4
1 27 332 361 344 1 4 17 9 2 5 9 5 3 286 42 1 0 0 0 10.741 -8.4 -12.4
1 28 307 432 397 5 2 16 6 3 7 6 4 4 339 63 0 0 0 0 10.9 -8.3 -18.2
1 29 341 429 411 3 2 13 8 1 6 8 5 5 343 53 1 0 0 0 11.054 -8.3 -12.4
1 30 288 364 338 7 2 13 6 2 8 8 3 2 289 46 2 0 0 0 7.095 -8.3 -21.6
2 31 330 429 397 5 5 13 8 4 8 7 2 3 350 47 0 0 0 0 3.753 -9.3 -28.6
3 32 275 413 379 5 2 14 10 2 9 4 3 7 325 53 1 0 0 0 3.069 -9 -27.2
2 33 327 409 377 5 2 13 8 2 6 8 5 4 322 54 1 0 0 0 4.06 -9 -18
2 34 379 431 404 4 7 13 8 3 5 8 2 4 344 57 0 0 0 1 4.086 -8.8 -15.4
2 35 349 428 393 5 4 18 6 3 8 6 3 5 342 55 0 0 0 0 3.318 -8.6 -21.6
3 36 311 420 399 5 2 16 8 5 10 4 1 3 328 61 1 0 0 0 2.707 -8.6 -29.2
1 37 337 400 370 3 0 18 6 2 6 8 7 5 315 51 1 0 0 0 9.687 -8.6 -11
4 38 331 462 423 2 2 14 4 2 7 7 6 6 368 62 0 0 0 0 4.955 -8.5 -7
2 39 344 411 377 4 3 15 6 1 8 7 5 3 329 52 1 0 0 0 4.03 -8.4 -14.6
1 40 378 434 403 2 2 11 9 2 9 8 4 3 343 56 1 0 0 0 10.673 -8.3 -18.8
2 41 357 424 397 4 5 14 10 1 4 7 5 4 342 51 0 0 0 0 3.554 -9.4 -16.8
2 42 352 432 404 4 5 16 9 5 6 7 2 3 345 55 2 0 0 0 3.84 -9.4 -21
2 43 357 412 379 4 5 12 6 2 5 9 5 5 336 44 1 0 0 0 3.979 -9.4 -12.6
2 44 343 427 409 4 3 12 7 3 5 8 5 4 351 44 0 0 0 1 4.222 -9.3 -16.2
3 45 285 414 386 5 2 13 9 2 6 4 2 7 319 65 2 0 0 0 2.978 -9.2 -15.6
3 46 333 443 423 3 2 13 8 3 7 5 4 6 353 57 1 0 0 0 4.734 -8.8 -17
4 47 400 464 423 2 1 12 6 0 5 7 6 7 371 62 0 0 0 1 5.202 -8.7 -1.4
2 48 334 425 392 5 4 16 5 5 9 10 3 4 342 47 0 0 0 0 3.142 -8.7 -26.8
3 49 323 424 392 5 1 17 7 4 10 4 1 4 345 49 1 0 0 0 2.52 -8.7 -28
1 50 318 425 392 5 1 15 4 3 8 8 4 3 335 60 0 0 0 0 10.462 -8.7 -17
2 51 361 429 404 5 4 13 8 4 6 7 3 3 348 50 0 0 0 0 3.708 -9.3 -24.4
2 52 352 410 380 4 4 11 6 2 5 9 6 5 329 48 1 0 0 0 3.879 -9.2 -11.8
73
1 53 326 373 348 3 1 16 8 4 4 12 4 3 299 39 0 0 1 0 11.983 -9.1 -18
2 54 362 428 398 4 3 14 6 3 6 7 5 4 344 53 0 0 0 0 4.206 -9.1 -16.4
3 55 295 414 388 5 2 13 9 3 9 4 3 7 321 58 1 0 0 0 3.243 -9 -26.2
1 56 352 402 382 3 1 21 8 2 3 6 7 6 315 55 2 0 0 0 12.661 -8.9 -6.4
3 57 315 425 391 5 3 17 8 4 8 2 1 4 335 63 1 0 0 0 2.572 -8.8 -23.4
4 58 337 434 406 4 1 9 5 2 10 11 3 4 343 56 0 0 0 0 10.095 -8.7 -19.4
2 59 339 427 402 5 4 16 5 4 8 7 4 4 356 39 0 0 0 0 3.147 -8.6 -24.8
1 60 370 417 383 5 3 10 9 3 4 7 7 2 322 63 0 0 0 2 10.401 -8.6 -14.2
74
Appendix E: Gliclazide
Group
ID
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/ mol)
Calc Delta-G (kcal/ mol)
4 1 215 358 341 2 0 8 2 3 6 4 6 2 293 42 2 0 0 0 2.511 -7.7 -8.4
2 2 220 359 343 2 0 8 3 1 4 2 4 3 293 49 1 0 0 0 8.482 -7.6 -3.6
4 3 246 340 324 2 5 7 3 1 4 2 4 4 276 46 2 0 0 0 4.206 -7.6 -2.2
3 4 231 347 336 4 1 8 3 1 5 3 3 1 276 55 2 0 0 0 8.445 -7.6 -6.2
2 5 235 351 336 0 0 8 4 1 6 1 3 4 273 59 1 0 0 0 8.436 -7.5 -3
4 6 234 348 333 4 0 9 2 3 6 7 5 1 286 38 0 0 0 0 3.062 -7.5 -17.2
4 7 215 365 363 1 1 4 2 3 6 3 3 3 300 45 0 0 0 0 2.662 -7.4 -9.8
4 8 222 352 345 5 0 8 6 3 7 4 2 2 283 45 1 0 0 0 0 -7.4 -24.8
4 9 243 363 344 1 4 6 5 2 2 6 3 3 298 44 1 0 0 0 4.431 -7.3 -4.4
1 10 245 342 332 1 1 9 5 1 5 0 6 2 274 49 1 0 0 0 8.967 -7 -7
4 11 213 358 342 2 0 7 2 4 5 3 5 2 292 45 2 0 0 0 2.526 -7.7 -7.8
2 12 218 358 340 2 0 9 3 1 8 2 4 3 296 41 1 0 0 0 8.481 -7.7 -12.4
4 13 262 342 334 2 5 7 3 1 5 2 4 4 277 46 1 0 0 0 4.396 -7.6 -6
3 14 219 348 327 4 1 8 3 4 5 3 2 1 279 51 2 0 0 0 8.46 -7.6 -12.4
2 15 224 352 329 0 0 9 5 1 5 1 4 5 273 58 1 0 0 1 8.442 -7.5 -1.2
4 16 215 364 352 1 0 4 2 2 6 2 3 2 299 48 1 0 0 0 2.667 -7.4 -5.4
1 17 239 341 319 1 1 7 2 1 6 2 9 5 257 59 1 0 0 0 8.105 -7.4 -1.4
4 18 233 346 328 4 2 9 2 4 5 7 5 1 285 37 0 0 0 0 2.73 -7.4 -17.4
1 19 250 344 319 1 1 7 4 1 4 4 7 2 262 60 1 0 0 0 8.915 -7.1 -1.2
1 20 228 341 318 1 1 10 2 3 5 5 7 1 275 43 0 0 0 0 8.206 -7 -8.4
75
4 21 215 361 351 2 0 9 2 3 4 4 4 2 302 40 2 0 0 1 2.497 -7.7 -3.2
2 22 214 359 345 2 0 10 3 1 6 2 4 3 290 50 1 0 0 0 8.481 -7.6 -7
4 23 240 341 338 2 6 8 3 1 5 2 5 3 275 47 2 0 0 0 4.197 -7.6 -3.8
3 24 229 348 330 4 1 10 3 4 6 3 3 1 287 41 2 0 0 0 8.448 -7.6 -16.2
2 25 224 352 332 0 0 9 5 1 5 1 4 5 273 58 1 0 0 0 8.442 -7.5 -3.2
4 26 225 347 329 4 1 8 2 4 2 7 5 1 291 35 0 0 0 0 2.619 -7.4 -12.4
2 27 243 362 343 1 1 8 3 1 5 2 3 4 288 56 1 0 0 0 8.537 -7.4 -2
4 28 220 349 345 5 0 9 6 3 5 3 3 2 279 48 1 0 0 0 1.575 -7.4 -20.6
4 29 226 365 358 1 1 5 3 3 6 3 4 3 307 36 0 0 0 0 2.605 -7.4 -13.4
1 30 246 341 317 1 1 7 2 1 7 2 10 5 255 59 1 0 0 0 8.194 -7.4 -3.2
4 31 215 361 351 2 0 9 2 3 4 4 4 2 302 40 2 0 0 1 2.516 -7.7 -3.2
2 32 214 359 345 2 0 10 3 1 6 2 4 3 290 50 1 0 0 0 8.478 -7.7 -7
4 33 240 341 338 2 6 8 3 1 5 2 5 3 275 47 2 0 0 0 4.293 -7.6 -3.8
3 34 229 348 330 4 1 10 3 4 6 3 3 1 287 41 2 0 0 0 8.447 -7.6 -16.2
2 35 224 352 332 0 0 9 5 1 5 1 4 5 273 58 1 0 0 0 8.444 -7.5 -3.2
4 36 225 347 329 4 1 8 2 4 2 7 5 1 291 35 0 0 0 0 2.637 -7.4 -12.4
4 37 243 362 343 1 1 8 3 1 5 2 3 4 288 56 1 0 0 0 1.549 -7.4 -2
4 38 220 349 345 5 0 9 6 3 5 3 3 2 279 48 1 0 0 0 2.649 -7.4 -20.6
1 39 226 365 358 1 1 5 3 3 6 3 4 3 307 36 0 0 0 0 8.095 -7.4 -13.4
4 40 246 341 317 1 1 7 2 1 7 2 10 5 255 59 1 0 0 0 2.786 -7.2 -3.2
4 41 216 358 346 2 0 9 2 3 4 4 6 2 299 38 1 0 0 0 2.476 -7.7 -7.6
2 42 225 358 349 2 0 9 3 2 7 2 4 3 296 41 1 0 0 0 8.488 -7.7 -12.4
3 43 219 348 331 4 1 7 3 4 5 3 3 1 288 41 1 0 0 0 8.448 -7.6 -16.4
2 44 219 352 334 0 0 9 5 1 5 0 4 5 273 59 1 0 0 0 8.439 -7.6 -3
4 45 220 348 328 5 1 8 2 3 4 7 5 2 275 50 0 0 1 0 3.078 -7.5 -12.2
4 46 228 349 344 5 0 8 6 3 4 4 2 2 286 42 1 0 0 0 1.52 -7.4 -20
4 47 224 365 356 1 1 5 3 3 7 3 3 2 299 45 0 0 0 0 2.627 -7.4 -13.4
4 48 213 357 335 2 2 7 5 1 5 5 3 4 281 53 1 0 0 0 2.891 -7.3 -8.2
4 49 256 358 344 5 1 9 3 2 2 5 5 3 289 49 2 0 0 0 2.963 -7.2 -5.8
1 50 228 340 319 1 0 8 2 1 7 3 5 4 276 42 0 0 0 0 8.224 -7 -8.6
76
Appendix F: Glimepiride
Group
Pose
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/ mol)
Calc Delta-G (kcal/ mol)
3 1 356 460 428 7 4 13 10 1 3 6 5 5 363 67 3 0 0 0 2.399 -9.2 -12.8
1 2 338 400 382 4 5 14 9 0 3 10 8 4 318 48 2 0 0 0 9.342 -9.1 -9
3 3 347 448 414 6 1 10 8 3 6 7 5 4 362 53 2 0 0 0 0.653 -9 -21
1 4 340 392 380 4 3 18 6 1 3 6 8 5 321 42 0 0 0 0 13.409 -8.8 -10.6
1 5 313 404 373 4 1 17 7 2 2 7 8 4 330 44 3 0 0 0 8.655 -8.6 -6
1 6 332 401 366 6 4 14 6 0 4 9 10 3 328 41 2 0 0 0 8.659 -8.4 -10.8
1 7 355 437 414 2 2 12 4 3 7 5 6 3 352 57 2 0 0 0 12.55 -8.2 -6.8
4 8 400 480 442 2 5 15 7 0 3 8 9 6 376 71 0 0 0 1 12.346 -8.2 1.2
4 9 373 500 467 5 0 15 7 3 6 10 5 1 392 76 2 0 0 0 12.096 -8.1 -12.6
2 10 381 465 430 4 2 18 6 1 9 6 4 3 373 63 0 0 0 0 5.738 -8 -17.2
3 11 363 462 432 7 4 16 8 2 4 5 4 4 371 64 2 0 0 0 2.383 -9.2 -15.4
1 12 332 400 375 4 4 14 9 0 2 9 11 4 313 52 2 0 0 0 9.272 -9.1 -6.4
3 13 343 450 415 6 1 10 8 4 4 7 6 3 366 52 1 0 0 0 0.32 -9 -21.4
1 14 328 394 378 2 2 18 7 1 5 7 8 4 317 45 1 0 0 0 13.319 -8.7 -9.4
1 15 316 401 370 4 1 16 7 2 2 8 8 3 320 51 3 0 0 0 8.668 -8.6 -4.6
4 16 395 450 431 3 2 10 4 1 7 9 9 3 364 53 1 0 0 1 11.153 -8.5 -6
1 17 301 400 373 6 3 16 7 1 5 9 8 5 316 49 0 0 0 0 7.921 -8.5 -18.6
1 18 394 499 469 0 3 10 6 3 9 5 5 7 394 70 2 0 0 1 11.397 -8.2 -5.4
2 19 442 501 470 0 5 14 5 0 6 8 8 4 400 70 1 0 0 0 6.287 -8.1 3.2
4 20 387 474 436 1 2 14 8 0 4 10 9 5 372 66 2 0 0 1 12.364 -8 2.6
77
3 21 360 460 430 7 4 14 9 2 3 5 5 4 375 57 1 0 0 0 2.423 -9.2 -18.8
1 22 357 404 385 3 1 14 8 0 3 7 12 2 318 54 5 0 0 0 9.264 -9 2
3 23 328 447 401 6 1 10 8 3 6 6 6 3 355 60 2 0 0 0 0.457 -9 -19.6
1 24 333 393 359 3 2 18 7 1 5 8 7 4 313 48 2 0 0 0 13.372 -8.8 -8.8
4 25 401 452 420 3 2 10 4 1 5 9 10 3 362 58 1 0 0 1 11.147 -8.6 -1.4
4 26 396 481 436 2 3 15 8 0 4 10 9 4 377 69 1 0 0 1 12.311 -8.5 -0.8
1 27 345 417 392 3 3 10 8 0 6 7 9 6 340 41 1 0 0 0 9.403 -8.4 -14
2 28 449 505 480 2 0 15 5 1 10 5 8 4 408 64 2 0 0 0 6.669 -8 -9
4 29 370 491 462 5 0 18 7 5 7 9 3 2 377 81 1 0 0 0 12.089 -8 -19
4 30 359 510 477 4 1 15 8 4 7 7 4 3 409 68 2 0 0 0 12.081 -8 -17.6
3 31 350 465 432 7 4 15 8 2 5 5 5 4 377 59 2 0 0 0 2.41 -7.9 -18.2
1 32 338 401 382 4 4 15 9 0 4 9 10 3 315 51 3 0 0 0 9.305 -9.2 -8.2
3 33 346 451 417 6 1 10 8 3 5 7 6 4 364 54 2 0 0 0 0.5 -9.1 -19
1 34 309 393 368 8 1 14 5 0 4 12 6 3 316 47 0 0 1 0 8.914 -9 -14.8
1 35 351 390 367 4 3 16 5 1 4 8 8 4 316 44 1 0 0 0 13.503 -8.9 -8.2
4 36 401 452 430 3 3 12 4 1 8 8 8 3 362 58 2 0 0 1 11.092 -8.6 -4.8
1 37 329 402 379 4 0 17 9 2 1 6 6 4 328 46 2 0 0 0 8.63 -8.5 -9.4
4 38 366 465 419 0 3 13 9 1 1 7 6 5 357 79 1 0 0 0 11.995 -8.4 5
1 39 329 389 362 2 3 13 6 0 6 12 10 1 314 40 2 0 0 0 12.949 -8.3 -6.6
1 40 356 412 379 6 1 15 5 1 5 11 7 3 324 56 2 0 0 0 9.068 -8.2 -9.6
3 41 349 461 427 7 4 15 8 2 5 5 3 4 380 54 2 0 0 0 2.476 -9.2 -19.2
3 42 324 447 413 6 1 11 8 4 5 7 6 3 358 56 2 0 0 0 0.677 -9 -20.4
1 43 357 405 377 3 1 13 8 0 2 8 13 2 322 50 4 0 0 0 9.277 -9 1
1 44 327 402 376 4 1 13 7 2 2 8 8 4 323 48 2 0 0 0 8.646 -8.6 -7.2
4 45 379 478 442 2 3 13 7 0 5 10 9 4 377 66 0 0 0 0 12.295 -8.5 -5.4
2 46 378 512 486 2 2 12 9 1 6 5 7 3 415 66 2 0 0 0 6.92 -8.1 -8.6
1 47 336 397 376 7 4 14 8 1 6 7 3 4 301 67 0 0 0 0 6.655 -8 -20.6
4 48 368 498 472 4 1 17 8 2 8 9 5 3 383 80 1 0 0 0 12.092 -7.9 -15.4
1 49 330 411 378 3 2 19 5 0 7 8 7 4 327 53 2 0 0 0 12.408 -7.9 -6
1 50 380 424 401 5 4 14 8 0 4 6 9 2 348 47 1 0 0 0 8.804 -7.9 -13.2
78
Appendix G: Glipizide
Group
Pose
10A Lig Waters
10A Prot Waters
10A Prot-Lig Waters
Prot-Lig HB
Prot-Lig HF
Actual SWB
Absolute Displaced Waters
Contact Displaced Hydrophobic
Contact Displaced Bulk
Contact SWB
Contact SWH Prot HB
Contact SWH Lig HB
Total Matched Prot Waters
Total Indirect Displaced (moved)
Prot Waters
Broken Prot HB
Broken Lig HB
Same Charge/Polarity Clash
Trapped Lig Waters
RMSD
Docking Score (KCal/ mol)
Calc Delta-G (kcal/ mol)
4 1 334 375 360 6 3 16 5 0 2 13 6 3 299 47 1 0 0 1 10.613 -8.7 -4.2
4 2 390 417 393 7 2 18 8 1 4 7 5 4 335 53 2 0 0 0 12.266 -8.4 -15.8
4 3 343 383 356 5 1 17 5 0 4 10 7 7 301 49 0 0 0 1 11.563 -8.4 -7.4
1 4 376 485 452 8 0 18 5 3 7 9 5 2 382 72 1 0 0 0 9.501 -9.3 -19.6
4 5 368 423 398 4 3 16 8 2 7 6 5 2 350 43 1 0 0 0 11.741 -8.7 -21
3 6 343 388 377 8 1 17 5 0 4 14 3 3 311 48 1 0 0 0 3.427 -8.8 -13.6
1 7 375 384 373 5 2 22 5 0 4 10 6 4 308 47 0 0 0 0 9.176 -8.8 -9.8
1 8 397 432 409 3 5 15 5 0 3 10 4 7 338 65 3 0 0 0 7.808 -8.4 5.6
4 9 306 400 365 6 1 13 6 0 7 5 3 6 315 58 2 0 0 0 11.122 -8.6 -12.8
2 10 326 388 371 5 6 15 5 0 8 6 5 4 310 50 0 0 0 0 2.892 -8.6 -16.4
2 11 335 374 354 6 3 17 5 0 4 12 5 5 302 41 1 0 0 0 3.887 -8.8 -11
4 12 386 419 394 8 3 17 8 1 3 5 4 3 341 54 2 0 0 0 11.111 -8.4 -15.8
1 13 334 420 389 4 4 18 9 1 5 8 5 5 330 57 0 0 0 0 8.621 -8.7 -16.6
2 14 338 394 378 7 0 16 6 1 3 10 4 3 321 46 1 0 0 0 3.934 -8.8 -13.8
1 15 293 405 375 5 0 14 8 1 8 5 3 5 320 55 1 0 0 0 9.659 -8.7 -20.6
3 16 358 485 447 7 0 20 4 3 6 9 5 3 387 68 1 0 0 0 0.305 -9.2 -14.8
2 17 360 425 399 5 2 18 6 2 8 7 2 3 345 52 0 0 0 0 3.91 -9 -21.4
1 18 316 392 374 6 0 15 8 3 3 6 4 3 318 47 0 0 0 0 8.524 -8.7 -20.8
3 19 427 419 401 3 2 15 5 1 5 8 5 5 346 44 1 0 0 1 0.267 -9.1 -6
3 20 395 434 413 2 6 17 4 0 5 7 6 5 359 48 1 0 0 0 3.622 -8.7 -1.6
79
4 21 332 374 353 6 3 15 5 0 5 10 6 5 302 41 2 0 0 1 11.768 -8.8 -8.8
2 22 384 417 384 7 2 20 8 2 5 5 4 3 341 49 1 0 1 0 2.653 -8.8 -21.2
2 23 322 408 378 6 6 14 5 0 4 10 5 5 326 53 0 0 0 1 2.638 -8.6 -8.6
3 24 367 420 394 4 3 16 9 2 4 9 4 3 346 43 0 0 0 0 0.438 -9.2 -19.4
1 25 287 405 370 5 1 14 9 1 7 3 2 7 323 53 2 0 0 0 9.472 -8.9 -19
1 26 383 422 396 4 3 18 8 2 6 9 2 4 343 48 0 0 0 0 8.018 -8.7 -20.2
1 27 374 485 460 7 0 18 4 3 5 8 4 2 390 69 1 0 0 0 9.502 -8.7 -12.8
1 28 339 374 363 5 3 22 8 0 2 7 5 5 301 46 2 0 0 1 8.753 -8.8 -5.8
1 29 390 424 406 2 1 15 5 1 5 7 10 5 334 57 3 0 0 0 9.62 -8.5 0.6
3 30 277 355 331 11 3 17 7 2 2 6 2 4 293 39 2 0 0 0 1.311 -9.1 -23
4 31 334 372 351 6 3 16 6 0 3 9 6 5 294 49 1 0 0 1 11.027 -8.4 -7.4
2 32 370 415 388 7 2 17 8 1 4 7 4 3 336 52 1 0 0 0 3.959 -8.9 -18
1 33 350 422 395 4 3 19 10 0 4 4 4 4 337 59 1 0 0 0 9.444 -9.3 -12.4
1 34 349 383 359 8 4 19 3 2 4 12 4 3 302 53 1 0 0 0 7.678 -8.5 -12.6
4 35 370 483 455 8 0 15 4 2 7 9 5 2 389 65 1 0 0 0 11.78 -8.8 -17.4
4 36 367 418 388 5 5 20 7 2 6 9 5 4 339 46 0 0 0 0 10.721 -8.7 -20.8
4 37 357 412 392 2 3 10 5 0 4 8 6 8 336 45 1 0 0 1 11.533 -8.6 -0.2
2 38 384 435 409 2 3 16 4 1 6 10 6 4 352 52 1 0 0 0 3.907 -8.8 -4.4
1 39 388 424 394 2 3 13 6 1 5 6 7 5 347 46 1 0 0 0 10.616 -8.2 -7.4
1 40 365 409 388 5 3 15 4 0 6 9 5 7 323 55 2 0 0 0 9.436 -9 -6
4 41 383 415 393 7 2 17 8 2 2 6 4 3 337 53 2 0 1 0 11.771 -8.7 -13
3 42 356 372 352 4 2 17 8 0 4 9 6 4 296 45 0 0 0 1 1.344 -9.2 -11.6
1 43 330 395 362 7 0 16 7 2 3 7 4 4 314 54 1 0 0 0 9.389 -9.3 -15.8
1 44 347 426 393 4 3 16 9 2 4 9 4 4 337 57 0 0 0 0 10.34 -8.6 -16.6
2 45 351 416 393 6 7 17 5 0 7 9 6 5 337 47 2 0 0 0 2.661 -8.8 -13.2
3 46 288 407 368 5 0 14 9 1 7 5 2 5 327 51 1 0 0 0 3.415 -8.8 -21.4
1 47 397 434 397 3 5 14 5 0 3 10 5 6 348 57 1 0 0 1 8.707 -8.5 2
1 48 372 395 364 5 3 21 8 0 1 8 5 4 316 53 0 0 0 0 9.991 -8.5 -8.6
1 49 321 393 367 6 0 16 8 1 2 4 4 4 316 54 0 0 0 0 10.385 -8.9 -14
1 50 279 352 327 11 2 12 7 2 3 12 4 2 284 38 1 0 0 0 9.436 -9.4 -27
Abstract (if available)
Abstract
Molecular docking is a powerful tool in drug discovery. It intuitively presents invisible bonds and atoms in a visible way so that it makes drug discovery more efficient and affordable. In recent years, it has become one of the most commonly used methods in drug discovery. Drug design has shifted from a tool purely focusing on molecular interactions to a platform to study both pharmacodynamics and pharmacokinetic properties. In this research, molecular docking was performed to study ligand binding to sulfonylurea receptor 1 (SUR1), which is a regulatory subunit of the ATP-binding cassette (ABC) transporter. The abnormal activity of SUR1 is closely related to congenital hyperinsulinism and type 2 diabetes. Glibenclamide is a typical example of a sulfonylurea inhibitor of SUR1, and it is the only ligand with an available X-ray structure with SUR1. The research started from the molecular docking of glibenclamide and extended to other drugs in the sulfonylurea family. The binding energy of SUR-ligand complexes was calculated in both solvated and un-solvated states, and common characters of low free energy complexes were examined. The purpose of this research is to understand the most favorable conformation of sulfonylureas in the complex, discover the binding pattern of SUR1 – ligand complexes, and explore the energy calculations in solvated molecular docking.
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University of Southern California Dissertations and Theses
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Asset Metadata
Creator
Sun, Chentong (author)
Core Title
Molecular docking of sulfonylureas to the SUR1 receptor
School
School of Pharmacy
Degree
Master of Science
Degree Program
Pharmaceutical Sciences
Degree Conferral Date
2021-12
Publication Date
10/01/2021
Defense Date
09/30/2021
Publisher
University of Southern California
(original),
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Tag
autodocking,deprotonation,free energy,glibenclamide,hydrogen bonds,molecular docking,OAI-PMH Harvest,solvation,sulfonylureas,SUR1 receptor
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application/pdf
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Language
English
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Electronically uploaded by the author
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Advisor
Haworth, Ian (
committee chair
), Duncan, Roger (
committee member
), Tabancay, Angel Jr. (
committee member
)
Creator Email
chentong@usc.edu,sunchentong.99@qq.com
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC16021812
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UC16021812
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etd-SunChenton-10126
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Sun, Chentong
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University of Southern California Dissertations and Theses
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Tags
autodocking
deprotonation
free energy
glibenclamide
hydrogen bonds
molecular docking
solvation
sulfonylureas
SUR1 receptor