ROCS - GPU Technology Conference

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ROCS - GPU Technology Conference

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Shape Searching on the GPU

Paul Hawkins, Ph.D.

Applications Science Group Leader

phawkins@eyesopen.com

5/22/2013 © 2013 OpenEye Scientific Software


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?

5/22/2013 © 2013 OpenEye Scientific Software


The philOEsophy

There are only two fundamental descriptors

Shape

Electrostatics

5/22/2013 © 2013 OpenEye Scientific Software


Shape is a Fundamental Physical

Property of a Molecule.

Shape exists and can be measured & quantitated

5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


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…

5/22/2013 © 2013 OpenEye Scientific Software


Virtual Screening: a passing fad?

HTS

Virtual screening

Tanrikulu et al.,

Drug Disc. Today (2013)

5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


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

0.90

5/22/2013

© 2013 OpenEye Scientific Software


Today’s Topics


• Shape searching with ROCS – what do it?


5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


Overlay and alignment

.

Overlay centres of mass

.

Query conformer(s)

Database conformers

Optimise

.

.

Align along PMI’s

5/22/2013 © 2013 OpenEye Scientific Software


Shape Tanimoto

A

B

Overlap

A + B - Overlap

5/22/2013 © 2013 OpenEye Scientific Software


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.

5/22/2013 © 2013 OpenEye Scientific Software


Enrichment (1%)

ROCS: VS with known target structure.

Performance on diverse actives

50

Mean

Median

40

30

20

T-test

ROCS > GLIDE

p < 0.07

10

0

Glide Phase ROCS

X-ray ligand as query

Svensson et al., J. Chem. Inf. Model. 52, 225 (2012).

Variability:

|Mean-Median|

5/22/2013 © 2013 OpenEye Scientific Software


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.

5/22/2013 © 2013 OpenEye Scientific Software

Lobeline

10 mM


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

5/22/2013 © 2013 OpenEye Scientific Software


E(1%)

E(1%) X-ray = OMEGA conformation

30

OMEGA

X-ray

20

10

0

Mean

Median

5/22/2013 © 2013 OpenEye Scientific Software


ROCS: Summary

• Excellent VS

– Success does NOT require a bioactive

conformation for the query

– Better than docking

• Effective lead-hopping

– Shape != 2D

• Fast

– 1000-2000 conformers/second

• Up to 40 molecules/second

5/22/2013 © 2013 OpenEye Scientific Software


Today’s Topics



ROCS on the GPU – why more speed?

5/22/2013 © 2013 OpenEye Scientific Software


Shape Overlays per

Second

ROCS on the GPU: FastROCS

400000

300000

200000

100000

0

CPU

GPU

5/22/2013 © 2013 OpenEye Scientific Software


Moore’s Law

“I say,

if Gore invented

the Internet,

I invented the

exponential.”

– Gordon Moore

http://en.wikipedia.org/wiki/Moore's_law

5/22/2013 © 2013 OpenEye Scientific Software


Shape Overlays per Second

Riding Moore’s Law

3500

3000

CPU

600000

14% 44%

500000

GPU

2500

400000

2000

300000

1500

1000

200000

500

100000

0

Xeon 5450

Xeon 5560 (Nehalem)

0

C1060

C2050 (Fermi)

5/22/2013 © 2013 OpenEye Scientific Software


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

800,000

600,000

400,000

200,000

0

C1060 C2050 C2075 C2090 K10 K20

5/22/2013 © 2013 OpenEye Scientific Software


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+00

1 3 5 7

Number of individual K10 GPUs

(Note, each K10 has 2 physical GPUs on the board)

5/22/2013 © 2013 OpenEye Scientific Software


AUC

Keeping speed high

1.0

0.9

ROCS

FastROCS

0.8

0.7

0.6

0.5

400 200 100 50 25 10 1

Maxconfs

FastROCS is for scoring, not alignment

5/22/2013 © 2013 OpenEye Scientific Software


FastROCS in Practice

Database: 5 M cpds (ZINC: 10 confs/mol)

• 1 machine with 64GB of RAM and 4GPUs

– 30-40 seconds to search

• 2 machines with 32GB of RAM each and 8GPUs

– 15-20 seconds to search

ROCS = 1.5 CPU days

5/22/2013

© 2013 OpenEye Scientific Software


AUC FastROCS

ROCS != FastROCS

1

0.75

0.5

0.25

Higher Correlation

Lower Correlation

0

0 0.25 0.5 0.75 1

AUC ROCS

5/22/2013 © 2013 OpenEye Scientific Software


Why more speed? DIFFERENT work

ROCS @ 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

5/22/2013 © 2013 OpenEye Scientific Software


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

5/22/2013 © 2013 OpenEye Scientific Software


Summary

• Shape searching is very powerful

– Fundamental description => robust

– Shape != 2D

• FastROCS opens new avenues for research

• GPGPU – computing of the future

5/22/2013 © 2013 OpenEye Scientific Software


To try it out online

• Email me for the URL

phawkins@eyesopen.com

5/22/2013 © 2013 OpenEye Scientific Software


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

www.nvidia.com/GPUTestDriv

e

Questions?

Contact us

Paul Hawkins – FastROCS

phawkins@eyesopen.com

Devang Sachdev - NVIDIA

dsachdev@nvidia.com

@DevangSachdev

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OpenEye Scientific Software

For more information, please contact us:

business@eyesopen.com

support@eyesopen.com

www.eyesopen.com

+1-505-473-7385

5/22/2013 © 2013 OpenEye Scientific Software


Technology Adoption Lifecycle

%2.5 %13.5 %34 %34 %16

OpenEye GPGPU development

5/22/2013 © 2013 OpenEye Scientific Software


RMSD

Geometric similarity does not predict

success

RMSD to X-ray & AUC

OMEGA2 conformation

better

4

3

X-ray conformation

better

2

1

0

-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4

AUC(X) - AUC(O)

5/22/2013 © 2013 OpenEye Scientific Software


Speedup (Single GPU time / Multi-GPU time)

Scalability between drivers (4x

C2050)

4

3

High

is

Best

2

Ideal

260 driver

295 driver

1

1 2 3 4

Number of GPUs

5/22/2013 © 2013 OpenEye Scientific Software


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

1,000,000

0

1 2 3 4 5 6 7 8

Number of individual K10 GPUs

(Note, each K10 has 2 physical GPUs on the board)

CUDA

OpenCL

Ideal

5/22/2013 © 2013 OpenEye Scientific Software

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