Transcript Grid enabled in silico drug discovery BUI The Quang Prof. Vincent Breton Prof. Doman Kim Prof.

Grid enabled in silico drug
discovery
BUI The Quang
Prof. Vincent Breton
Prof. Doman Kim
Prof. NGUYEN Hong Quang
Prof. PHAM Quoc Long
FKPPL workshop May 2012
Laboratories involved
-
CNU, Gwangju, Korea
IFI, Hanoi, Vietnam
INPC, Hanoi, Vietnam
KISTI, Seoul, Korea
LPC, Clermont-Ferrand, France
FKPPL workshop , May 2012
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Content
• Activity in Korea
• Activity in Vietnam
• Activity in France
FKPPL workshop , May 2012
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Activity in Korea - Publication 1
Human maltase:
- A α-glucosidase, belongs to glycosides hydrolase
family 31 (EC 3.2.1.20 and 3.2.1.3) and located on
chromosome 7 with 868 amino acids and contains
five distinct protein domains.
- Important target in treatment of diabetes type 2.
FKPPL workshop , May 2012
Credit: Doman Kim
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Filtration process
454,000 chemical compounds from Chembridge
Scoring based on docking score
( 308,307)
Statistics of data challenge deployment
on WISDOM production environment
3016 compounds selected
Interaction with key residues
2616 compounds
selected
Key interactions
binding models
clustering
42 compound
selected
Total numbers of docking
308,307
Total size of output results
16.3 GB
Estimated duration by 1CPU
22.4 years
Duration of experiments
3.2 days
Maximum numbers of concurrent CPUs
4700 CPUs
Crunching Factor
2556
Distribution Efficiency
54.4 %
In vitro
test
FKPPL workshop , May 2012
Credit: Doman Kim 5
Inhibition on human maltase &
pancreatic α-amylase
Compound
No.
Lowest
Energy
M.W
Ki
(g/mol)
(μM)
IC50 (µM)
Type of
inhibition
160
140
Acarbose
No.17
No.18
17
18
-16.43
-16.44
473
429
19.8 ±1.2
19.6±0.9
58±4
55±3
Competitive
Competitive
Relative activity (%)
120
100
80
60
40
20
Acarbose
-12.62
645.61
19.4
52±4
Competitive
0
0 uM
10 uM
25 uM
50 uM
100 uM
Inhibitor
 Unlike acarbose, compounds 17 and 18 were competitive inhibitors
exclusively for HMA without any in vitro inhibition for human pancreatic
alpha-amylase.
FKPPL workshop , May 2012
Credit: Doman Kim
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Activity in Korea Publication 2
1) A global outbreak of Severe Acute
Respiratory
Syndrome
(SARS)
between March 2003 and July 2003
caused over 8,000 cases and 774
deaths (9.6%) (World Health
Organization).
2) The 3C-like protease (3CLpro) is
needed for SARS-CoV replication
and is a promising drug target.
World Health Organization. Summary of probable SARS cases with onset of illness from 1 November 2002 to 31 July
2003 (based on data as of the 31. December 2003). http://www.who.int/csr/sars/country/table2004_04_21/en/.
Credit: Doman Kim
FKPPL workshop May 2012
Virtual screening 3CL protease of SARS on
WISDOM production environment
Docking parameters:
Ga_run=50, Ga_pop_size=250, Ga_num_generation=27000, Ga_num_evaluation= 2500000
Virtual screening on WISDOM
production environment
Compound No
Free binding energy
(kcal.mol-1)
IC50 (μM)
1
-14.5
58.35 ± 1.41
2
-15.09
62.79 ± 3.19
3
-15.17
101.38 ± 3.27
4
-15.20
77.09 ± 1.94
5
-15.75
90.72 ± 5.54
6
-15.02
38.57 ± 2.41
7
-15.13
41.39 ± 1.17
308,307
compounds
54 compounds were selected for In vitro assay
FKPPL workshop , May 2012
Credit: Doman Kim
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Activity in Vietnam
• The WPE platform
– Used in WISDOM projects(Wide In Silico Docking On Malaria)
for discovery of medicine for malaria
– Developed by LPC Clermont-Ferrand laboratory
– Reduce many time for finishing these challenges
• The DIRAC platform
– DIRAC: Distributed Infrastructure with Remote Agent Control
– DIRAC forms a layer between a particular community and
various compute resources to allow optimized, transparent and
reliable usage
• Comparison between the WPE & DIRAC platform
– Performance
– Stability
– Capability of submission of pilot agent
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Comparison of performance
700
DIRAC
DIRACisisfaster
faster
than
thanWPE
WPE
600
WPE
WPEisisfaster
faster
than
thanDIRAC
DIRAC
Time (minute)
500
DIRAC
400
WPE 100
300
WPE 200
WPE 500
200
WPE 1000
100
0
100
500
1000
Number of tasks
5000
10000
 DIRAC submit faster pilot agent than WPE
 one WPE’s agent execute many task while one DIRAC’s agent
execute only one task
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Comparison of stability
Rate of WPE’s & DIRAC’s pilot agents is terminated by unknown
cause(test with Autodock)
30%
25%
20%
15%
10%
5%
0%
DIRAC
WPE 100
WPE 200
WPE 500
WPE 1000
Percentage of DIRAC pilot agent is terminated by unknown cause is
less than WPE platform
 Pilot agent of DIRAC is more stable than pilot agent of WPE
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Comparison of capability of
submission of pilot agent
Rate of pilot agent submission successful to grid
120%
100%
80%
60%
40%
20%
0%
DIRAC
WPE 100
WPE 200
WPE 500
WPE 1000
Rate of DIRAC pilot agent submission successful to grid is higher
than WPE platform
 DIRAC platform submits better pilot agent to grid than WPE
platform
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Result from INPC laboratory
• Database of natural products isolated from biodiversity
in Vietnam (~1000 ligands)
• Anti-malarial tests on 43 compounds with 2 biological
targets: chloroquine-susceptible T96 and chloroquine
resistant K1
• Ongoing research to look for compounds with antimalarial bioactivity by virtual screening on the
database of natural products (2011)
– Key protein: protein plasmepsin II (1LEE)
– Use of AUTODOCK software for virtual screening
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Activity in France
Design a virtual screening system for multi-user
Grid resource
Scheduler
Problem of virtual screening on grid
- Speed of machine are different
- Task arrive in random process
- Available duration of machine are random
 Find out the policy for maximizing the throughput of all users
Workflow of research
-
Find out the policy and prove by theory
Valid on the grid simulator SIMGRID
Programming scheduler on the DIRAC platform
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Thank you for your attention
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