Will Docking Work?(On My Target)

John J. IrwinUCSF Pharmaceutical Chemistry

ChemAxon, BostonSeptember 14, 2010

Acknowledgements• Current lab members

– Michael Mysinger, Pascal Wassam, Ryan Coleman, • Previous lab members

– Eddie Cao, Francesco Colizzi, Niu Huang– Kong Nguyen, Michael Carchia

• Brian K. Shoichet, PI• NIH GM71896• Companies

– ChemAxon, Molinspiration, OpenEye, Molecular Networks, Xemistry

Screening for Novel Inhibitors byMolecular Docking .

dock

Test high-scoring molecules

Why is Docking Difficult? Binding sites are complicatedLots of interactions to considerEverything in competition with water

Kd = e-ΔG/RT

ΔGbind = ΔGinter - ΔGsolv

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Predicted docking posetested by crystallography (1)

CTX-M beta lactamase. Chen Y, Shoichet BK. Molecular docking and ligand specificity in fragment-based inhibitor discovery. Nature Chemical Biology 5, 358-364 (2009).

Teotico DG, Babaoglu K, Rocklin GJ, Ferreira RS, Giannetti AM, Shoichet BK. Docking for fragment inhibitors of AmpC ß-lactamase. PNAS 106 (18), 7455-60 (2009).

Babaoglu K, et al. Austin CP, Shoichet BK. Comprehensive mechanistic analysis of hits from high-throughput and docking screens against beta-lactamase. J Med Chem 51, 2502-11 (2008).

Predicted docking posetested by crystallography (2)

Graves AP, Shivakumar DM, Boyce SE, Jacobson MP, Case DA, Shoichet BK. Rescoring docking hit lists for model cavity sites: predictions and experimental testing. J Mol Biol 377, 914-34 (2008). T4 lysozyme. L99A

Predicted docking posetested by crystallography (3)

Graves AP, Shivakumar DM, Boyce SE, Jacobson MP, Case DA, Shoichet BK. Rescoring docking hit lists for model cavity sites: predictions and experimental testing. J Mol Biol 377, 914-34 (2008).

T4 lysozyme. L99A/M102Q

Cytochrome C Peroxidase W191G

Hermann JC, Marti-Arbona R, Fedorov AA, Fedorov E, Almo SC, Shoichet BK, RaushelFM. Structure-based activity prediction for an enzyme of unknown function. Nature

448,775-9 (2007).Use of DOCK to predict the substrate of an enzyme of previously unknown function.

Predicted docking posetested by crystallography (4)

Met230

Asp235

Wat308

Leu177

Met230

Asp235

Met230

Asp235

Wat308

Leu177

Asp235

Met230

Leu177

Asp235

Met230

Leu177

Asp235

Met230

Asp235

Met230

Asp235

His175

Met230

Asp235

His175

Met230

Brenk R, Vetter SW, Boyce SE, Goodin DB, Shoichet BK. Probing molecular docking in a charged model binding site. J Mol Biol 357, 1449-70 (2006). CCP W191G

Predicted docking posetested by crystallography (5)

L118 F114

V111

Q102

V103

L84 V87

L121

Wei BQ, Weaver L, Ferrari AM, Matthews BM, Shoichet BK. Testing a flexible-receptor docking algorithm in a model binding site. J Mol Biol 337 (5), 1161-82 (2004). M102A

Wei BQ, Baase WA, Weaver LH, Matthews BW, Shoichet BK. A model binding site for testing scoring functions in molecular docking. J Mol Biol 322, 339-55 (2002). M102Q

Predicted docking posetested by crystallography (6)

Powers RA, Shoichet BK. Structure-based approach for binding site identification on AmpC ß-lactamase. J Med Chem 45, 3222-34 (2002).

Why is Docking Difficult to Automate?

Structure Interpretationof structure

Why is Docking Difficult to Automate?

Structure Interpretationof structure

Database preparation

The ZINC Database

35 million compoundscommercially availablestructures calculatedmultiple conformationsproperties (charge, solv, etc…)links to suppliers

Free to the community

Multiple subsets13.4 M drug-like (Lipinski)3.5 M lead-like (Oprea…)400 K fragment-like (Astex, …)

Availlable in popular formatsSMILES, SDF, mol2, flexibase

Irwin & Shoichet JCIM 2005

http://zinc.docking.org

Rapid Turnover!Updated continuously (~10,000 new today)Over 2 million new compounds per yearOver 1 million depletions per year

New Search Tool

Search 32M+ molecules in seconds

Benefits of using ChemAxonfor ZINC Search

• Very fast search– Degrades very slowly with database size

(currently 32 million)

• Simple interface to our existing system

• Supports many concurrent queries– degrades gracefully

ChemAxon/ZINC IntegrationResults BrowserQuery Interface

Webserver

CGI Script(Python)

Curl (3)

Tomcat Server

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Why is Docking Difficult to Automate?

Structure Interpretationof structure

Database preparation

Running docking:Site preparationSoftware configurationParameter choicesFile manipulations

dock

AutomatedDockingPipeline

Irwin*, Shoichet, Mysinger et al, J Med Chem, 2009 52(18), 5712-5720

Try Docking Four Ways

#4#3Finer#1

Polarized#2Coarser

AMBER

Sam

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Scoring

Thus four docking runs with four different parameter sets.

Start with a PDB Code

Pick a PDB Code for Docking. Click DOCK!

Why is Docking Difficult to Automate?

Structure Interpretationof structure

Assessment.Did docking work?

ACE (automated)

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Assessment: Review Docking Hits

Browse using Chimera or PyMOL

Self-Assessment1. Remove ligand from receptor 2. Rebuild ligand without crystal bias

3. Dock ligand and 100 phyisically-matched decoys using 4 parameter sets 4. Evaluate pose-fidelity, enrichment

Scoring Polarized Normal

Coarser 3.61 Å / 1% 1.32 Å / 9% Sa

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Finer 1.32 Å / 2 % 2.02 Å / 3%

Rankbest

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RMSD (Å) vs xtal

DUD

Experiment: re-dock crystallographic ligand and 100 property-matched decoysUsing the 85 Astex-95 benchmark PDB structures.

Pose Fidelity Does Not Predict Enrichment

Large Benchmark

15/38 (39%)DUD-3827/114 (24%)Gold-114

29/85 (34%)Astex-85

Benchmark Success Rate

Fully automatic docking starting from PDB code(and ligand specification if required)

Irwin*, Shoichet, Mysinger et al, J Med Chem, 2009 52(18), 5712-5720

5%

AND

1398/7750 (18%)PDB

DUD

A Multi-Ligand Metric

13,500 Protein targets 1825 Ligand sets for targets

X-ray, <= 2.5 ANon-covalent organic ligand

5 or more ligands10uM affinity or better

733 Ligand

sets

7408PDB

codes

http://www.ebi.ac.uk/chemblhttp://www.rcsb.org/pdb

DUD

Multi-LigandEnrichment Results

• 7408 PDB structures with ligands• 4826 Automatic docking starts (65%)• 4018 Automatic docking completes (54%)• 2500+ Good enrichment => Docking works

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How Well Does Docking Work?Less Hopeless Than We Feared

• 134/345 targets attempted• Showing results for 114

65(57%)

41(36%)

ACE (automated)

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Enrichment Depends on Decoys

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∆adjusted logAUC = adjusted logAUC full scoring – adjusted logAUCvdW-onlyMulti-ligand

metrics

VdW-Only Scoring is Not an Adequate Substitute of a Full Scoring Function

delta=adj logAUCfullscoring -adj logAUC vdWonly

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