Will Docking Work? (On My Target) - ChemAxon€¦ · (On My Target) John J. Irwin UCSF...
Transcript of Will Docking Work? (On My Target) - ChemAxon€¦ · (On My Target) John J. Irwin UCSF...
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
small large large
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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
plin
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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
mpl
ing
Finer 1.32 Å / 2 % 2.02 Å / 3%
Rankbest
worst
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LigandRank?
5%
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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Adj
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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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