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Dr. Haifeng Chen
Shanghai Jiaotong University
Computer Aided Drug Design
and Case Study
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2013 Nobel Chemistry Prize
The prize was awarded for laying the foundation for the computer models used to understand and predict chemical processes.
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Reference Book
Xiaojie Xu and Tingjun Hou. Computer Aided Drug Desing. Chemistry Industry Press, 2004.
Kaixian Chen. Computer Aided Drug Design: Principal, Method and Appication. Shanghai Science and Technology Press, 2000.
Textbook of Drug Design and Discovery. Edited by Povl Krogsgaard-Larsen, Tommy Liljefors, Ulf Madsen,published by Taylor & Francis,2002.
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Reference Book
A. R. Leach. Molecular Modelling. Principles and Applications. Addison Wesley Longman, Essex, England, 2001.
Broad introduction to many aspects of molecular modeling and computational chemistry techniques, covering basic concepts, quantum and molecular mechanics models, techniques for energy minimization, molecular dynamics, Monte Carlo sampling, free energy simulations, and drug design applications
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SCI Article of Undergraduate Student
1. Z. Li, J. Han, H. F. Chen*. Chem. Biol. Drug Des. 72:350-359, 2008.(2005)(Chinese Academy of Sciences)
2. Z. Li, H. Zhang, Y. Li, J. Zhang, H. F. Chen*. Chem Biol Drug Des 77:63-74, 2011. (2005)
3. F. Qin, Y. Chen, Y. X. Li, H. F. Chen*. J. Chem. Phys. 131: 115103, 2009. (2005)(SJTU)
4. H. Zhang, F. Qin, W. Ye, Z. Li, S. Ma, Y. Xia, Y. Jiang, J. Zhu, Y. Li, J. Zhang, H. F. Chen*. Chem Biol Drug Des 78:427-437, 2011. (2008)(Duke University)
5. G.W. Yan, Y. Chen, Y. Li, H. F. Chen*. Chem Biol Drug Des 79:916-925, 2012. (2011)(University of Michigan State)
6. S.Y. Ma, W. Ye, D. J. Ji, H.F. Chen*. Medicinal Chem. 9: 420
– 433, 2013. (2009) (Purdue University)
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Pig Flu/A H1N1
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From 1997- now
Avian Flu/H7N9
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2002-2003
SARS
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Human and animal infectious diseases
Plague (6th century) - Death rate : 30%~100%
Cholera (18th century) - Death rate : 30%~100%
Anthrax (19th century) - Death rate : 20% Ebola virus (1976)
- Death rate : 50%~90% HIV (1980)
- Death rate : 61% Mad cow disease (1985)
- Death rate: 100% Avian flu (1997)
- Death rate : 33.3% Pig flu (2009)……
H7N9 (2013)
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Drug discovery of post genomics
Function genomics
Target discov
ery
Target evaluat
ion
Lead discovery
Lead optimization
Preclinic test
Clinical trail
Market
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Drug development flowchart
New Chemical Entity
Structure optimization
Preclinical test (ADMET)
New drug research application
Clinical trail (I II III)
New drug application
Post market research
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Drug design flowchart
Drug Discovery Today 7: 315-323 (2002)
Target Identification
Drug screening, Potential
drug discovery, side effects
Dise
ase
analysis
Clin
ic test
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Virus analysis of avian flu
N Engl. J. Med. 2013,20:1888-1897.
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Drug target
Success target : 300-400
Receptor Enzyme Ion channel Nucleic acid
Science 2013, 341:84-87.
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Success Cases
HIV-1 Protease Inhibitors in the market:
Inverase (Hoffman-LaRoche, 1995)
Norvir (Abbot, 1996)
Crixivan (Merck, 1996)
Viracept (Agouron, 1997)
Drug discovery today 2, 261-272 (1997)
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Merck HIV-1 protease drug (Crixivan)
1987
Sequence Function Clone
Crystal
Inhibitor research
Screening L-F35524
Human test
Clinical test for 4000 samples
FDA approve: 42 days
1987-1988
1989
1989
1989-1992
1993
1993-1996
1996.3.
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Challenge of drug development
New chemical entity: Difficult Time: long (10-15 years) Cost : expensive (800 million US$) Method: do not speed (Combine Chem. & HTS) How to speed?
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Challenge of drug development
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Main methods of CADD
Statistics Math
Statistical mechanics
Quantum mechanics
QM/MM
Molecular mechanics
Molecular Dynamics
Monte Carlo Simulation
Enzyme catalyst
Conformer Search
Classic MD
Ab initio MD Newton Second Law
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20 20
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Most used technologies
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Computer aided drug design Method
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Molecule
Structure
Biological activity(Φ)
IC50, Ki …
Cl
Cl
Hasch (1962): Hansch analysis
Richard Cramer III (1987): CoMFA
Gerhard Klebe (1994): CoMSIA
Lowis (1997): HQSAR
Vapnik (1992/2001):SVM
Tin Kam Ho (1995/2003):Random Forest
QSAR,Quantitative Structural-Activity Relationship
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Molecules Are Not Numbers!
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Molecular Descriptors
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Hansch classic QSAR
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HQSAR(Holograph QSAR)
Fragment size
Number of fragments
Atom types
Bond types
Atom hybridization
Stereocenters
PLS analysis result
QSAR Comb. Sci. 23:36-55, 2004.
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Principle and application
of 3D-QSAR
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Method of 3D-QSAR
Bioactivity
3D-QSAR Model
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3D-QSAR
CoMFA (Comparative Molecular Field Analysis )
CoMSIA (Comparative Molecular Similarity Indices Analysis )
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The hypothesis condition of CoMFA
All molecules
Have same interaction mechanism with the same kind of receptor (or enzyme, ion channel,etc.)
Have identical binding sites in the same relative geometry.
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Create a 3D database
Calculate charges for each of compounds
(Gasteiger-Hückel)
Minimize the structure (Tripos force field)
Calculate the steric and electrostatic field energies (Steric and electrostatic contributions were cutoff
to a value of 30 kcal/mol)
Do regression analyses (partial-least squares (PLS))
Perform using full cross-validation (leave one-out method)
r2 value (q2)
3D-QSAR steps
Contour maps
Alignment
Training set and test set (3:1)
Conformer
search
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Conformer Search
Gridsearch
Multisearch
Random search
System search
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Alignment Rules
Pharmacophore-based alignment Pharmacophore is a spatial arrangement of
atoms or functional groups which response for bioactivity
Structure-based alignment
MCSS(Maximum Common Substructure) or
skeleton structure
Dock-based alignment Active conformer could align together by the
results of molecular docking
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Grid and probe atom
Probe atom
Box must cover the structures.
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The type of probe atom
Sp3 C+
Sp2 O-
Sp3 N+
H+
Ca2+ …
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Potential function of CoMFA
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Partial Least Square
QSAR equation
PLS
Contour Maps
Predictions
QSAR Table = SYBYL MSS
Bio
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Construct CoMFA Model
PLS Component
Field contribution
Steric and electrostatic contour plots
Relationship between EA and PA
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Interpretation of CoMFA
For drug design, the most powerful tool is to find the relationship
between fields and bioactivity, then design
new lead compounds.
Green: bulk group
Yellow: small group
Red: negative charge
Blue: positive charge
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Advantages of CoMFA vs Classical QSAR
Visualization
Higher predictive power
Truly three-dimensional, shape-dependant nature of CoMFA descriptors
CoMFA analyzes the interaction energy of an entire ligand rather than arbitrarily selected substructure of the ligand
CoMFA has been accepted by many as the ultimate solution to the problem of correlating chemical structure and biological activity
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Shortcomings of CoMFA
CoMFA parameters do not include hydrophobicity
Need to specify initial “alignment rule” and “active conformation”
Often fail when a few molecules are very dissimilar from all others
The results from one CoMFA analysis are not easily compared with another one
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Factors of influence CoMFA
Active conformer
Aligment rules
Probe atom
Lattice size
Orientation of alignment molecular set
Step size
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CoMSIA
Steric fields
Electrostatic fields
Hydrophobic fields
Hydrogen bond donor fields
Hydrogen bond acceptor fields
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Potential function of CoMSIA
CoMSIA is not sensitive to changes in orientation of
the superimposed molecules in the lattice.
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Interpretation of CoMSIA
Yellow: hydrophobic ↑ ; White: Hydrophobic ↓
Cyan: hydrogen bond donor ↑; Purple: hydrogen bond donor ↓
Magenta:hydrogen bond acceptor ↑; Red: hydrogen bond acceptor ↓
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Drug Design of HIV-1
Protease Inhibitor
Student : Guanwen Yuan(Shanghai
High School)
Supervisor: Haifeng Chen(SJTU)
Shanghai High school-SJTU Join Program
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Content
Backgrounds 1
Methods 2
Results 3
Discussions 4
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About AIDS
Infect : 60,000,000
Death : 30,000,000
1,050,000 (2008) 23.3 billion $ China
Up to now, no bacterin
WHO
http://www.cmt.com.cn/xshy/gr/AIDS2010/AIDS2010/201007/t20100714_263494.html
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Vacinne design
Envelope trimer
Science 2013,DOI: 10.1126/science.1245627
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AIDS of China
2006 2007 2008 2009 20100
2000
4000
6000
8000
10000
12000
14000
Num
ber
of D
eath
Year
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HIV-1 Life Cycle
Nature Medicine
5, 740 - 742 (1999).
Integrase Inhibitors
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HIV-1 drug target
CCR5 1IKY 2013 HIVRT 1HNI 1995 HIVIN 3L3V 2010 HIVPT 1HXW 1995
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HIV RT inhibitor
HIV Protease inhibitor
HIV Integrase inhibitor
Cocktail therapeutics
AIDS
Cocktail Types
Drug resistance
New anti-HIV inhibitor
Therapeutic method
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Combination of drugs
Dolutegravir(整合酶抑制剂)+ Abacavir (阿巴卡韦)(非核苷HIVRT inhibitor)+ Lamivudine(拉米夫定)(核苷类似物)(DTG-ABC-3TC)
EFV (非核苷HIVRT inhibitor)(泰诺福韦)-TDF (核苷类HIVRT inhibitor)(替诺福韦酯)-FTC(核苷类HIVRT inhibitor)(恩曲他滨)
N Engl J Med. 7, 2013; DOI: 10.1056/NEJMoa1215541
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Background
HIV Protease (HIVPR)
HIV-1 codes p55 and p60
HIVPR can break pre protein and activate
protein. Specific enzyme of virus.
HIVPR is the key enzyme of mature for
HIV-1 virus.
Drug target
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Binding mode between inhibitor and HIVPR
作用机理:
抑制剂与酶结合→使酶失去催化活性→阻断HIV在体内的复制→
抗AIDS的药效
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PNAS 109:20449–20454, 2012.
Simulation open and close of HIVPR
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Motion with PCA
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Research Methods
Computer Aided Drug Design
Molecular Dynamics (MD) Simulation
3D-Quantitative Structure-Activity
Relationship (3D-QSAR)
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Data Set
Bioorg Med Chem Lett 2003, 13, 3601-3605.
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Molecular dynamics simulation
Molecular dock: M17-HIVPR, M35-HIVPR
AMBER8.0 & Parm99SB force field
5000ps simulation - 298K
Result analysis
Hydrogen bond
Hydrophobic interaction
Binding free energy
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Molecular Dock
Calculating the binding free energy
Finding the molecular mechanism between ligand and receptor
Finding the relationship between bioactivity and binding free energy
Using with other methods(Find active conformer to build CoMFA model)
Virtual screening
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The AutoDock Software
Developed by AJ Olson’s group in 1990.
AutoDock uses free energy of the docking molecules using 3D potential-grids
Uses heuristic search to minimize the energy.
Search Algorithms used: Simulated Annealing
Genetic Algorithm
Lamarckian GA (GA+LS hybrid)
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Docking complex
Ligand
Receptor
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Docking preparing - ligand
Assign charges
Align with tempale molecule
Define rotatable bonds
Merge non-polar hydrogens
Write .pdbq ligand file
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Receptor preparing
Delete water and ligand in complex
Add polar hydrogen
Load charge (Kollman_all)
Minimize hydrogen atom
Add solvation parameters
Write .pdbqs protein file
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Autodock result
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Correlation between Binding Free Energy and bioactivity
-16 -15 -14 -13 -12 -11 -10 -9 -8 -7
4
5
6
7
8
9
Lo
g(1
/EC
50
)
Binding free energy (kcal/mol)
pIC50=0.759 - 0.503*△G (n=76, r=0.739, F1,75=89.217, SD=0.861)
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3D-QSAR Study
Construct structure-bioactivity model, predict drug bioactivity and virtual screen
Molecular alignment, then calculate force parameter
PLS parameter represents the quality of model. R2 ,accuracy
Test set can evaluate model
Contour plot
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3D-QSAR Study
SYBYL7.0 program package
Training set & Test set (3:1)
(Random class)
Molecules Alignment
CoMFA & CoMSIA models
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Results
Molecular Dynamics Simulation
The most important hydrophobic and
hydrogen bonding interactions
Action Mechanism of Inhibitors
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Stability of complex
0 25 50 75 100 125 150 1750.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
RM
SF
(Å
)
Residues
M17-HIV PR
M35-HIV PR
M35 < M17
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Hydrogen bond
0 1000 2000 3000 4000 50002345678345678
Time (ps)
Asp30-F3(M35)
Asp25-O1(M35)B
Dis
tance (
Å)
Ala28-O6(M17)
Asp25-O6(M17)
A
Bioactivity:M35>M17 M35/HIVPT: Two strong hydrogen bonds M17/HIVPT: Two weak hydrogen bonds
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Hydrophobic interaction
1 2 3 4 5 6 70
20
40
60
80
100
Popula
tion (
%)
Native contact
M17
1 2 3 4 5 6 7 8 910
M35
Bioactivity:M35>M17 M35/HIVPT: 10 M17/HIVPT: 7
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Binding free energy
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Binding mode and key residue
Common residues: Ile50(A) Ile50(B) Asp25(A) Ile83(A) Ala28(A)
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Conclusion of MD simulation
Similar action mechanism both systems have hydrogen bond with catalytic
residue of Asp25 of HIVPR
Key residues: Ile50(A), Ile50(B), Asp25(A), Ile83(A),
and Ala28(A)
Hydrogen bond offered by the OH
Strong hydrophobic interaction offered by the benzene ring
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Result of 3D-QSAR
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Force Combination of CoMSIA
406080
SEHDASEDASEHDSEHASEASEDSEH
F
Force fieldSE
6
8
1/S
EE
0.50.60.7
R2
0.8
1.0Q
2
Best CoMSIA model:SEHA
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Prediction ability
1.5 2.0 2.5 3.0 3.51.5
2.0
2.5
3.0
3.5
4.0
2.0
2.5
3.0
3.5
Ca
lcu
late
d a
ctivity
Experimental activity
CoMSIA
Training set
Test set
CoMFA
r2 of test set : 0.939 (CoMFA) 0.825 (CoMSIA)
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CoMFA & CoMSIA
X: bulk & positive
charge
Y: small volume &
positive charge
Contour plot analysis
Field + —
Steric green yellow
Electro
static
blue red
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Contour plot of CoMSIA
X: hydrophilic substitute
Y: hydrophobic & hydrogen bond donor
Field + -
Hydrophob
ic
Orange white
Hydrogen
bond
acceptor
cyan purple
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Conclusion of 3D-QSAR
X: bulk and positive groups
M30(4-COOCH3) > M28(4-CH3) > M29(4-CN) > M31(4-COOH); M1(4-H) > M21(4-F)
Y: small and positive charge groups
M14(4-CH3) > M15(4-CN) > M13(4-CF3) > M16(4-COOCH3) > M18(4-CH2OH) > M20(4-CONH2) > M17(4-COOH).
X:hydrophilic group
M32(4-CH2OH)>M30(4-COOCH3); M32>M31(4-COOH); M32>M28(4-CH3); M32 >M29(4-CN)
Y: hydrophobic and hydrogen bond donor group
M16(4-COOCH3)>M17(4-COOH); M14(4-CH3)> M19(4-CH2NH2)
OO
O
OO
O
X
X
Y
Y
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MD vs 3D-QSAR
MD: two hydrogen bonds between M35(F3/O1)and Asp25/Asp30
3D-QSAR: hydrogen bond favour regions F3/O1
MD: M35 has hydrophobic interactions with Ile50(A), Ile50(B), Ile83(A), and Ala28(A).
3D-QSAR: Benzene is covered by hydrophobic favour regions.
The result of MD is consistent with that of 3D-QSAR.
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Comparison with previous work
1.5 2.0 2.5 3.0 3.5 4.01.5
2.0
2.5
3.0
3.5
2.0 2.5 3.0 3.5 4.0
Pre
dic
ted
activity
Experimental activity
This work
r2 = 0.970
Previous work
r2 = 0.867
997.2219.0189.0
461.0116.0246.0151.0191.0
5156.0252.0148.01198.0246.0
____
_______
_____
OFYFdiY
pdoHbondYpYOXFYFX
pYpYpYpXpX
II
IINNN
BmrBPA
Quality: same Quantity:better
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Conclusion
MD simulation suggests interaction mechanism, key hydrogen bond and hydrophobic interactions.
3D-QSAR method constructs robust prediction model.
The results of MD are agreement with those of 3D-QSAR.
Better than previous works.
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Pulications
Insight into the Binding Mode of HIV-1 Protease Inhibitor Using Molecular Dynamics Simulation and
3D-QSAR. Chem Biol Drug Des 2012. (IF=2.46)
Insight into the Stability of Cross-β Amyloid Fibril from Molecular Dynamics Simulation. Biopolymers 93: 578-586, 2010. (IF=2.82)
Conformational Selection or Induced Fit for Brinker and DNA Recognition. Physical Chemistry Chemical Physics. 2011 (IF =4.06)
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Forecoming research of HIV-1 protease
Complex of HIV-1 PR and nelfinavir
Mutant residues: V32I I50V/L I54M/V I84V L90M A71V
Drug resistant?
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Thank You!