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FKPPL workshop May 2012 BUI The Quang Prof. Vincent Breton Prof. Doman Kim Prof. NGUYEN Hong Quang...
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Transcript of FKPPL workshop May 2012 BUI The Quang Prof. Vincent Breton Prof. Doman Kim Prof. NGUYEN Hong Quang...
FKPPL workshop May 2012
BUI The Quang
Prof. Vincent Breton
Prof. Doman Kim
Prof. NGUYEN Hong Quang
Prof. PHAM Quoc Long
Grid enabled in silico drug discovery
FKPPL workshop , May 2012 2
Laboratories involved
- CNU, Gwangju, Korea- IFI, Hanoi, Vietnam- INPC, Hanoi, Vietnam- KISTI, Seoul, Korea- LPC, Clermont-Ferrand, France
FKPPL workshop , May 2012 3
Content
• Activity in Korea• Activity in Vietnam• Activity in France
FKPPL workshop , May 2012 4
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.
Credit: Doman Kim
Activity in Korea - Publication 1
FKPPL workshop , May 2012 5
Scoring based on docking score( 308,307)
454,000 chemical compounds from Chembridge
Interaction with key residues
3016 compounds selected
2616 compounds selected
Key interactionsbinding models
clustering
In vitro test
42 compound selected
Filtration process
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 %
Statistics of data challenge deployment on WISDOM production environment
Credit: Doman Kim
FKPPL workshop , May 2012 6
Inhibition on human maltase & pancreatic α-amylase
Inhibitor
0 uM 10 uM 25 uM 50 uM 100 uM
Rel
ativ
e ac
tivity
(%)
0
20
40
60
80
100
120
140
160
AcarboseNo.17 No.18
Compound No.
Lowest Energy
M.W
(g/mol)
Ki
(μM)IC50 (µM) Type of
inhibition
17 -16.43 473 19.8 ±1.2 58±4 Competitive
18 -16.44 429 19.6±0.9 55±3 Competitive
Acarbose -12.62 645.61 19.4 52±4 Competitive
Unlike acarbose, compounds 17 and 18 were competitive inhibitors exclusively for HMA without any in vitro inhibition for human pancreatic alpha-amylase.
Credit: Doman Kim
FKPPL workshop May 2012
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/.
Activity in Korea - Publication 2
Credit: Doman Kim
FKPPL workshop , May 2012 8
Docking parameters:
Ga_run=50, Ga_pop_size=250, Ga_num_generation=27000, Ga_num_evaluation= 2500000
Virtual screening on WISDOM production environment
Virtual screening 3CL protease of SARS on WISDOM production environment
54 compounds were selected for In vitro assay
308,307 compounds
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
Credit: Doman Kim
FKPPL workshop , May 2012 9
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
FKPPL workshop , May 2012 10
Comparison of performance
100 500 1000 5000 100000
100
200
300
400
500
600
700
DIRAC
WPE 100
WPE 200
WPE 500
WPE 1000
Number of tasks
Tim
e (m
inu
te)
DIRAC is faster than WPE
WPE is faster than DIRAC
DIRAC submit faster pilot agent than WPE one WPE’s agent execute many task while one DIRAC’s agent
execute only one task
DIRAC is faster than WPE
WPE is faster than DIRAC
FKPPL workshop , May 2012 11
Comparison of stability
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
DIRAC WPE 100 WPE 200 WPE 500 WPE 10000%
5%
10%
15%
20%
25%
30%
Rate of WPE’s & DIRAC’s pilot agents is terminated by unknown cause(test with Autodock)
FKPPL workshop , May 2012 12
Comparison of capability of submission of pilot agent
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
DIRAC WPE 100 WPE 200 WPE 500 WPE 10000%
20%
40%
60%
80%
100%
120%
Rate of pilot agent submission successful to grid
FKPPL workshop , May 2012 13
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 anti-malarial bioactivity by virtual screening on the database of natural products (2011) – Key protein: protein plasmepsin II (1LEE)– Use of AUTODOCK software for virtual screening
FKPPL workshop , May 2012 14
Activity in France
Design a virtual screening system for multi-user
SchedulerGrid resource
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
FKPPL workshop , May 2012 15
Thank you for your attention