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1 est Drive K20 GPUs! Experience The Acceleration Run Computational Chemistry Codes on Tesla K20 GPU today Sign up for FREE GPU Test Drive on remotely hosted clusters rive

2 Shape Searching on the GPU Paul Hawkins, Ph.D. Applications Science Group Leader

3 Today s Topics Shape similarity & virtual screening why should you care? Shape searching with ROCS why do it? ROCS on the GPU why more speed?

4 The philoesophy There are only two fundamental descriptors Shape Electrostatics

5 Shape is a Fundamental Physical Property of a Molecule. Shape exists and can be measured & quantitated

6 Where can we use shape? Virtual screening More effective than 2D & docking Lead-hopping Shape analogues are not graph analogues Shape comparisons are readily interpretable Molecular alignment No requirement for (manual) atom matching Pose generation/prediction Matching a binding site or a bound ligand

7 Virtual Screening What is it? A ranking method to probabilistically place active compounds higher than inactive Why do it? Cuts costs and time in experimental screening How do we do it? Property, F prints/2d, docking, p cores, shape

8 Virtual Screening: a passing fad? HTS Virtual screening Tanrikulu et al., Drug Disc. Today (2013)

9 Where can we use shape? Virtual screening More effective than 2D & docking Lead-hopping Shape analogues are not graph analogues Shape comparisons are readily interpretable Molecular alignment No requirement for (manual) atom matching Pose generation/prediction Matching a binding site or a bound ligand

10 Why do we like shape? Similarity in shape predicts similarity in biology Good neighbourhood behaviour IC50 = 10 nm IC50 = 10 nm Path (2D) similarity 0.12 Shape (3D) similarity /22/ OpenEye Scientific Software

11 Today s Topics Shape searching with ROCS what do it?

12 OpenEye Software Package OEChem TK Cheminformatics & molecule handling FILTER Remove undesirables QUACPAC Tautomers & charges VIDA & Vivant Visualization & communication BROOD Fragment replacement OMEGA 3D conformations ROCS Shape alignment and scoring FRED & HYBRID Docking and posing POSIT Ligand-guided pose prediction in a binding site EON Electrostatic scoring SZYBKI MMFF94 structure optimisation & entropy SZMAP Solvent mapping & thermodynamics

13 OpenEye Software Package OEChem TK Cheminformatics & molecule handling FILTER Remove undesirables QUACPAC Tautomers & charges VIDA & Vivant Visualization & communication BROOD Fragment replacement OMEGA 3D conformations ROCS Shape alignment and scoring FRED & HYBRID Docking and posing POSIT Ligand-guided pose prediction in a binding site EON Electrostatic scoring SZYBKI MMFF94 structure optimisation & entropy SZMAP Solvent mapping & thermodynamics

14 Given ROCS One active molecule in 3D conformation Conformations of molecules to be searched ROCS Rigidly aligns database molecules to query. 1,000-2,000 conformers/sec Scores alignment using shape and color. TanimotoCombo = Shape Tanimoto + Color Tanimoto

15 Overlay and alignment. Overlay centres of mass. Query conformer(s) Database conformers Optimise.. Align along PMI s

16 Shape Tanimoto A B Overlap A + B - Overlap

17 Shape Tanimoto: Gold Standard Is metric (follows triangle inequality) Is an objective function (has gradients, first and second derivatives). Fast to compute for single overlays. Easy extension to color (chemical features). Optimization generates alignments.

18 Enrichment (1%) ROCS: VS with known target structure. Performance on diverse actives 50 Mean Median T-test ROCS > GLIDE p < Glide Phase ROCS X-ray ligand as query Svensson et al., J. Chem. Inf. Model. 52, 225 (2012). Variability: Mean-Median

19 Lead-hopping with ROCS: Histamine H1 J. Med. Chem. 55, 7054 (2012). Chlorprothixine 1nM ROCS Not previously known as active on H1. Phentolamine 15 mm Find known drugs with new activity using ROCS. Lobeline 10 mm

20 Which is the best query conformation? Run ROCS on DUD (dud.docking.org) Crystallographic ligand as query Two query conformations of crystallographic ligand X-ray conformation Lowest energy OMEGA conformation Compare virtual screening performance

21 E(1%) E(1%) X-ray = OMEGA conformation 30 OMEGA X-ray Mean Median

22 ROCS: Summary Excellent VS Success does NOT require a bioactive conformation for the query Better than docking Effective lead-hopping Shape!= 2D Fast conformers/second Up to 40 molecules/second

23 Today s Topics ROCS on the GPU why more speed?

24 Shape Overlays per Second ROCS on the GPU: FastROCS CPU GPU

25 Moore s Law I say, if Gore invented the Internet, I invented the exponential. Gordon Moore

26 Shape Overlays per Second Riding Moore s Law CPU % 44% GPU 0 Xeon 5450 Xeon 5560 (Nehalem) 0 C1060 C2050 (Fermi)

27 Shape Overlays per Second Riding Moore s Law 2,000,000 1,800,000 1,600,000 1,400,000 1,200,000 1,000, , , , ,000 0 C1060 C2050 C2075 C2090 K10 K20

28 Conformers per Second GPU Scaling 9.E+06 8.E+06 7.E+06 6.E+06 5.E+06 4.E+06 3.E+06 2.E+06 1.E+06 0.E Number of individual K10 GPUs (Note, each K10 has 2 physical GPUs on the board)

29 AUC Keeping speed high ROCS FastROCS Maxconfs FastROCS is for scoring, not alignment

30 FastROCS in Practice Database: 5 M cpds (ZINC: 10 confs/mol) 1 machine with 64GB of RAM and 4GPUs seconds to search 2 machines with 32GB of RAM each and 8GPUs seconds to search ROCS = 1.5 CPU days 5/22/ OpenEye Scientific Software

31 AUC FastROCS ROCS!= FastROCS Higher Correlation Lower Correlation AUC ROCS

32 Why more speed? DIFFERENT work 40 mols/second; fast enough? FastROCS: not just ROCS, but faster Database searching in interactive time Better than 2D, probably faster Large scale clustering of databases

33 FastROCS: Database clustering Find shape holes in compound collection Find shape holes and fill them, pharma -> vendor Compare/contrast two collections Anonymously compare collections, pharma <-> pharma Shape!= 2D Drug repurposing Cluster known drug collections MDDR, CMC

34 Summary Shape searching is very powerful Fundamental description => robust Shape!= 2D FastROCS opens new avenues for research GPGPU computing of the future

35 To try it out online me for the URL

36 Test Drive K20 GPUs! Experience The Acceleration Run Computational Chemistry Codes on Tesla K20 GPU today Sign up for FREE GPU Test Drive on remotely hosted clusters e Questions? Contact us Paul Hawkins FastROCS phawkins@eyesopen.com Devang Sachdev - NVIDIA Stream other webinars from GTC Express: e/gtc-express-webinar.html

37 OpenEye Scientific Software For more information, please contact us:

38 Technology Adoption Lifecycle %2.5 %13.5 %34 %34 %16 OpenEye GPGPU development

39 RMSD Geometric similarity does not predict success RMSD to X-ray & AUC OMEGA2 conformation better 4 3 X-ray conformation better AUC(X) - AUC(O)

40 Speedup (Single GPU time / Multi-GPU time) Scalability between drivers (4x C2050) 4 3 High is Best 2 Ideal 260 driver 295 driver Number of GPUs

41 Conformers per Second CUDA Scaling? High is Best 8,000,000 7,000,000 6,000,000 5,000,000 4,000,000 3,000,000 2,000,000 1,000, Number of individual K10 GPUs (Note, each K10 has 2 physical GPUs on the board) CUDA OpenCL Ideal

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