drug hpc solution for the discovery platform drug ... · computational chemistry in pharma r&d...

DRUGDISCOVERYPLATFORM

HPC Solution for the Drug Repositioning Problem

Andrea R. BeccariDrug Discovery Platform Manager


Summary

• R&D Challenge in Pharmaceutical industry

• Computational Chemistry in Pharma R&D

• LiGen™

• HPC Application

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R&D in Pharmaceutical industryProductivity

Nature Reviews Drug Discovery 11, 6-8 (January 2012)


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R&D in Pharmaceutical industryEfficiency


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R&D in Pharmaceutical industryProbability of Transition: (pTS)

Nature Reviews Drug Discovery 9, 203-214 (March 2010)

4 product enter the market out of 100 R&D discovery programs


R&D in Pharmaceutical Industry

• Reduce failure rate– 24 programs for 1 market drug

• Reduce time– From 10 to 13 years for 1 market drug

• Reduce costs– From 0.8 to 2 billions for 1 market drug

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Challenges


R&D in Pharmaceutical industry

DefinitionUse a market drug for another indication

ProReduced time to market and failure rate

ConThe molecule could not be modified

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Drug Repositioning


Computational Chemistry in Pharma R&D

Computational chemistry supports all the phases of drug discovery process:

HPC allows to– Use more complex theoretical models– Dramatically reduce calculation time– Simulate huge systems

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• 4th Call of IMI: Technology and Molecular Disease Understanding

– Understanding and optimizing binding kinetics in drug discovery

Rationale:Kinetic of binding of candidate drugs strongly correlates with efficacy in humanBudget:> 100 Mio euro

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Computational Chemistry in Pharma R&DNeed for better models and tools


LiGen™

• Commercial and open source programs do not full fill all of our requirements

• Use proprietary technologies is a competitive advantages Vs competitors

• None of the other tools are designed to run on real HPC architectures

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Why Develop a new tool ?


LiGen™

• Dompé [Since 2005]– Andrea R. Beccari– Simone Lorenzi (Docking Specialist)

• CINECA [Since 2005]– Carlo Cavazzoni (Super Computing Applications)– Andrew Emerson (High Performance Systems)

• University of Parma [Since 2010]– Gabriele Costantino (Full professor)– Claudia Beato (Design of Experiment)

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The Team


In the field of molecularmodeling, docking is a methodwhich predicts the preferredorientation of one molecule to asecond when bound to eachother to form a stable complex.Knowledge of the preferredorientation in turn may be usedto predict the strength ofassociation or binding affinitybetween two molecules usingfor example scoring functions.

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LiGen™What is Molecular Docking


LiGen™

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Map The Cavity of the Protein


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Spring DockingFlexible Pharmacophoric Docking


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LiGen™Docking Result


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Design of Experiment

0123456789

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exp0

1ex

p04

exp0

7ex

p10

exp1

3ex

p16

exp1

9ex

p22

exp2

5ex

p28

exp3

1ex

p34

exp3

7ex

p40

exp4

3ex

p46

exp4

9ex

p52

exp5

5ex

p58

exp6

1ex

p64

exp6

7ex

p70

exp7

3ex

p76

exp7

9ex

p82


Benchmark

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Glide XP 72,4% 161,42 173,92 335,34

Ligen 75.5% 9,30 41,0 50,30

Autodock 85,3 % 9,83 397,08 406,91

% RMSD< 3 A

Averagepocket time (s)

Average dock time(s)

AverageTotal time (s)

Dataset: Redocking of 171 complexes (PDBbind core set and MW < 500)


LiGen™

Knights Ferry Beta Application Decision: Approved!

LiGen modules have been designed to be at the same time flexible and highlyefficient from a computational point of view (use of C++ and STL at high leveland proprietary C/C++ algorithms at low level), with particular attention tomodern and future Many Integrated Core (MIC) architecture.In agreement with Intel a porting to experimental Knights Ferry processor isongoing, which represents an extremely promising platform for HTVSapplication

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Intel® Beta testing


LiGen™

The ProblemFind a market drug that effectively bind a biological target.

Costs for performing real experiments1 market drug Vs 200 Biological Targets: 40K euro8K market drugs Vs 200 Biological Targets: 320M euroNumber of experiments: 1.6MSuccess rate : 0.5%

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The Drug Repositioning Problem


LiGen™

Cost for performing docking simulations

3M hours = 300K euroNumber of simulation = 720MSuccess rate = 0.01%

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HPC Solution for Drug Repositioning Problem

8KMarket Drugs

30KTargets

16KNear to Market

3M hours


Preliminary Results

During the Validation

We have selected 32 market drugs coming frommolecular docking simulations and we haveexperimentally tested against TRPM8 that is a relevanttarget for prostatic cancer.

1 market drugs shows, a never reported before, relevantbiological activity on this target.

Patent filing is on going.

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DRUGDISCOVERYPLATFORM Thank You !

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drug hpc solution for the discovery platform drug ... · computational chemistry in pharma r&d...

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