1. SimBioSys Inc.© 2003http://www.simbiosys.ca/ eHiTS: Novel algorithm for fast, exhaustive flexible ligand docking and scoring Zsolt Zsoldos, Aniko Simon, Irina Szabo, Zsolt Szabo, David Fung and A. Peter Jonson SimBioSys Inc., © 2003 Contents: ● Introduction: docking methods, exhaustive search definition ● Method: new docking algorithm implemented in the eHiTS software ● Scoring function: surface map based, including weak interactions ● Validation results and summary http://www.simbiosys.ca/

2. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Contents: Introduction Introduction Categorisation of the docking algorithms Definition of exhaustive docking search The search space size New docking algorithm of the eHiTS software Scoring function Validation results

3. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Y et A nother D ocking A lgorithm, YADA, yada... GOLD DOCK FlexX

4. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Exhaustive Conformation and Pose Search in our definition Discretisation must be fine enough to differentiate any atom movement >=0.5Å Rotation and dihedral sampling must be finer than 5° 30° sampling can miss perfect hydrohob fit by 1.5Å clashes PDB code: 1HRI ~7Å PDB code: 1CX2

5. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Search Space Size Number of poses to examine with sampling defined: Translations(0.5Å) * Rotations(5°) * Dihedrals(5°) = 20 3 * 72 3 * 72 n ~ n=6 rot.bonds => 2*10 20 poses per ligand Brute force evaluation 2000/s => 3 billion years Stochastic methods explore a tiny fraction of the space with no guarantee to find the best or even any good-enough solutions

6. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Contents: new docking algorithm Introduction New docking algorithm of the eHiTS software: Overview of the algorithm Rigid fragment docking Graph matching by clique detection Flexible chain fitting Scoring function Validation results

7. SimBioSys Inc.© 2003http://www.simbiosys.ca/ eHiTS algorithm overview: Divide and Conquer Ligand is divided into rigid fragments and connecting flexible chains All rigid fragments are docked independently Graph matching Flexible chain fitting Local energy minimisation Patent pending algorithm:

8. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Rigid fragment docking based on Chemical feature mapped polyhedra Polyhedron shrink-wrapped onto molecular surface (Connolly) Chemical feature flags on vertices Analogue cavity representation Rapid mapping of ligand and cavity polyhedra D D D D A A

9. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Graph matching by clique detection Each rigid fragment is now individually docked to several alternative sites Task is to find sets of poses such that: fragments can be linked by flexible chains they do not bump into each other Graph nodes: ligand fragment poses Graph edges: pose pairs at distance compatible with chain length Cliques encode docking solutions

10. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Flexible chain fitting Find chain conformation to link given pair of fragments: Double diamond latice to start from Tweak the chain to fit end points and avoid boundary (deterministic)

11. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Contents: scoring function Introduction New docking algorithm of the eHiTS software Scoring function: Surface map based ranking score Chemical feature flags Weak (secondary) interaction flags Validation results

12. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Surface map based ranking score Chemical property flags are mapped onto 0.5Å resolution Connolly surface Receptor surface point weights determined by depth in pocket Flag compatibility matrix score for receptor-ligand contacts Exposed receptor points get penalty based on depth value

13. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Feature flags indicate properties H-bond Donor: {D/d} H-bond Acceptor: {A/a} Hydrophobic flags: {H/h} Aromatic Pi-stack:ring {R}, center {O}, edge {E} Partial charges: {p/n} Formal charges: {P/N} Metal ions and ligands: {M/m} HdE nhR HR HO DApnmE

14. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Weak interaction flags Secondary (weak) H-bond donor flags are assigned to Carbon atoms in polar environment (e.g. in aromatic ring, next to Nitrogen) Heteroatoms in aromatic rings get secondary hydrophobic flags in direction of  electrons Secondary flags contribute to score and avoid penalties PDB code: 1AHA

15. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Contents: validation results Introduction New docking algorithm of the eHiTS software Scoring function Validation results: Examples: 1NIS, 1TDB, 1SRJ, 1FKG, 3CPA, 4SLI Graph and table of RMSD results on validation set Speed performance in different modes Summary

16. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 1NIS Stick & ball = X-ray crsytal structure ligand pose Closest (0.6Å RMSD) Top rank (0.9Å RMSD) Closest solution found by GOLD had 3.5Å RMSD

17. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 1TDB, that GOLD has failed to dock Stick & ball = X-ray crsytal structure ligand pose Closest (1.3Å RMSD) Top rank (3.7Å RMSD)

18. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 1SRJ, where “FlexX failed due to structural errors” Stick & ball = X-ray crsytal structure ligand pose Closest (0.6Å RMSD) Top rank (2.4Å RMSD)

19. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 1FKG, “too complex task for FlexX” Stick & ball = X-ray crsytal structure ligand pose Closest (1.1Å RMSD) Top rank (1.8Å RMSD)

20. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 3CPA, where DOCK failed Stick & ball = X-ray crsytal structure ligand pose Closest (0.93Å RMSD) Top rank (1.16Å RMSD)

21. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Example: PDB code 4SLI, where DOCK failed Stick & ball = X-ray crsytal structure ligand pose Closest (0.61Å RMSD) Top rank (0.65Å RMSD)

22. SimBioSys Inc.© 2003http://www.simbiosys.ca/ RMSD results on the validation set The Astex/CCDC validation set of GOLD was used: 105 PDB to tune parameters 200 PDB complexes to test

23. SimBioSys Inc.© 2003http://www.simbiosys.ca/ eHiTS speed Seconds per ligand on single CPU Linux PC 2.4GHz Pentium 4, 512MB RAM VHTS mode employs an SQL database to store rigid fragment poses and re-use it for other ligands having the same fragment

24. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Summary Advantages of the eHiTS software: Exhaustive search – don't miss a potential drug! High accuracy – the most important Deterministic – no need to wait for a lucky day Fully automated - no manual setup, seed selection Highly configurable scoring function Very fast - extremely High Througput Screening of large databases or virtual libraries http://www.simbiosys.ca/

25. SimBioSys Inc.© 2003http://www.simbiosys.ca/ Acknowledgements Team: Irina Szabo, Zsolt Szabo, Aniko Simon, David Fung, A. Peter Johnson and Zsolt Zsoldos Funding support by Canadian government grants: NRC - IRAP project #411461 GeoDock SR & ED project (2001) NRC - IRAP project #468906 EnerMin SR & ED project (2002)