Molecular Simulation and Design in
Drug Discovery
Jianhua Shen
Drug Discovery and Design Center
Shanghai Institute of Materia Medica
Chinese Academy of Science
Our Research
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Disease
Alzheimer, HIV, Diabetes and Cardiovarscular disease
Biomedical Molecules
Acetylcholine esterase (AChE), β secretase, HIV reverse
transcriptase (HIV RT),
K+ Channel, Nuclear Receptor, Gelsolin, CXCR4 and GABAA
receptor, etc.
Simulation (molecular dynamics technique)
Ligand-protein interaction (binding and unbinding processes)
Conformational motion of protein
Design (flexible molecular docking technique)
Ligand Compound Discovery for disease treatment
MD Simulation: Find an Open-Closing
Switch in channel of AChE
close
open
Minimize distance (nm)
0.8
0.6
open
0.4
0.2
AChE — Hup A — Water
close
0.0
0
500
close
1000
1500
2000
2500
Time (ps)
3000
3500
4000
4500
500
Steered MD Simulation of Hup A Entering
and Leaving the Channel of AChE
Leave
Enter
Hup A takes effect very fast
and has long time inhibition !
JACS, 2002
Force and Interactions During Hupzine
A Enter into and Leave off the channel
6
5
4
3
2
1
0
D 72
D 72
1
3
0
15
10
5
0
D72
15
D72
Water Bridge Hydrophobic
6
D72
D7 2
D72
D72
D7 2
D 72
D72
9
2
0
18
12
6
0
12
3
D 72
HBond
D72
D 72
D72
D 72
D 72
4
10
5
0
800
Force (pN)
800
600
400
200
0
-200
0
100
200
30 0
400
500
600
Time (ps)
700
800
900
1 000
1100
Channel Bottom → Channel Mouth
600
400
200
0
-200
0
100
20 0
300
400
500
600
Time (ps)
Channel Mouth → Channel Bottom
JACS, 2002
Movie of Hupzine A Leave from Channel of AChE
Water Molecule & Cation–Pi Interaction in
the Channel of AChE
20
Cation-Pi Binding Energy
number of water
Channel Bottom → Channel Mouth
15
5
4
3
2
1
0
10
5
0
100 200 300 400 500 600 700 800 900 1000 1100
0
0
1
2
3
Nu mber of Water Molecule
5
4
3
2
1
0
0
100
200
300
400
500
600
700
Time (ps)
Channel Mouth → Channel Bottom
Water molecules act as lubricant to
facilitate HupA to move in the channel !
J. Phys. Chem. 2002
Long
Time
Simulation
of HIV-RT
Open and
CloseMD
 Solvate
Effect Provides
the Energy
forDomain
HIV RT Domain
Motion !
Motion
Open → Close
Close → Open
Ligand
Pro tein Potential E nergy Change
(kcal/mol)
DNA
Free
1000
No solvate effect
800
600
400
Close → Open
Add solvate effect
200
0
0
1
2
3
4
5
6
7
8
9
10
SimulationTime(ns)
JMB 2002
Calculation for Binding
Affinities
Target Protein
Virtual High Throughput
Drug Screening
Chemosynthesis
Compound
database
Bioassay
R2
N
N
ACD 3D
ACD SC
MDDR
CNPD
300,000
2,000,000
100,000
50,000
R1
MD Simulation for Ligand
and Protein Interaction
N
Virtual Combinatorial
Library Design
Platform of Drug Design Aided
by Super Parallel Computer
Computer Aided Design of Anti-alzheimer
Lead Compound Reaches nano-Mol Activity
Peripheral Site
9 nM
14 nM
DOCKING
Link
7 µM
100 µM
New Compound
1997
Active Site
1998
1999
2000
Drug discovery based on the structure of
PPAR nuclear receptor for anti-diabetes
• Database with 2300,000
compound molecules
virtually screened for
PPARγ
• 19 compounds selected
and tested. 7 active
compound found.
• Chinese Natural Product
Database with 50,000
compounds virtually
screened and 2 active
natural compounds found
Successful Examples of Computer Aided
Ligand Discovery in DDDC
Disease
Target
Method
Result
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Cardiovascular
Arrhythmia
Arrhythmia
Alzheimer
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Alzheimer
Cancer
Diabetes
PFA receptor
3D-QSAR
3 compound activity than gingkgo lactone
K+ channel
3D-QSAR
1 compound in preclinical phase
K+ channel Virtual Screen
1 nature compound activity >1000s TEA
AChE
Virtual Screen &
de novo design 1 compound with nano-mol activity
β secretase
Virtual screen
1 Compound with µMol activity
MMP
ZGB design
1 compound with nano-mol activity
PPARγ
Virtual screen
7 compounds and 2 natural compound
with sub-µMol activity
Faculty of Drug Discovery and Design Center
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Prof. H. Jiang
Prof. K. Chen
Prof. J.K. Shen
Dr. J. Gu
Dr. J. Shen
Dr. X. Luo
Dr. X. Shen
Dr. W. Zhao
Dr. H. Liu
Head
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3 Post-doc and 31 students
Combinational Chemstry
Computational Chemstry
Biomolecular Simulation
Computer Aided Drug Design
Molecular Biology
Natural Chemistry
Medical Chemstry
Computing Resources
Hardware
• SGI Origin 3400 64 CPU 32GB Memory and 2100MB Hard disk
• SGI Origin 3200 4 CPU
• Alpha Cluster 32 CPU 32GB Memory and 500MB Hard disk
• 7 SGI visualization workstations
• 2 Compaq Alpha Workstations
• 398 CPU SW-1 Supercomputer (Shanghai Supercompter Center)
Software
Insight II
Molecular Simulation
Sybyl
Drug Design
G98, Nwchem
Computaional Chemstry
Dock5.0, Pdock
Drug Screening
Xplor, Amber, EGO, Gromacs
Molecular Dynamics Simulation
Database
Cheminformatics Database (Accelrys Inc.)
Chinese Natural Product Database CNPDTM
Thank You