Fast Computational Method for Fragment Growing and Joining Using Molecular Fields

1. Fast Computational Method for Fragment Growing and Joining Using Molecular Fields Dr Martin J Slater

2. Cresset BMD: Who are we? • Cresset was founded in 2002 by innovator Andy Vinter • We provide and continually develop a suite of unique cutting edge molecularmodelling software for drug discovery. • We have clients from big pharma, agrochem, biotech and academia

3. Cresset’s unique technology • It uses a condensed 3D representation of the electrostatic, hydrophobic and shape properties of molecules together with the full fields. = Positive = Negative = Shape = Hydrophobic Field Points 2D Representation What chemists see? 3D Molecular Electrostatic Potential (MEP) What proteins see? What our CPUs see?

4. Not using XEDs Interaction of Acetone and Any-OH from small molecule crystal structures XEDs make fields work • Field patterns from Cresset’s proprietary XED force field reproduce experimental results Using XEDs Experimental XED adds p-orbitals to get better representation of atoms

5. Biologically Relevant Molecular Comparisons Bioisosteric groups Bioisosteres

6. View fields Structure Fields Experimental (Data from small molecule xray structures) Field points give you new insights into your molecule

7. Comparing 2D and 3D metrics Similar 2D=3D_FS 2D = 3D_FS 2D=3D Dissimilar 2D=3D_FS

8. Example - Higher 3D Sim 2D sim = 0.1 (other methods=0.3) 3D field sim = 0.82

9. Example - Higher 3D Sim 2D sim = 0.2 141 454 3D sim = 0.7

10. Spark’s Approach • Find bioisosteres by replacing sections of the molecule Valdecoxib Etoricoxib Rofecoxib 12nM

11. Spark’s Approach Select a region to replace and remove these atoms

12. Spark’s Approach • Select a region to replace and remove these atoms • Search database for matching fragments • (geometric search only) • (search runs on fragment conformations) Wrong distance

13. Spark’s Approach • Select a region to replace and remove these atoms • Search database for matching fragments • (geometric search only) • (search runs on fragment conformations) Wrong angle

14. Spark’s Approach • Select a region to replace and remove these atoms • Search database for matching fragments • geometric search only • (search runs on fragment conformations) • Form Products • minimise and add field points Good match

15. Spark’s Approach • Select a region to replace and remove these atoms • Search database for matching fragments • geometric search only • search runs on fragment conformations • Form Products • minimise and add field points • Score 0.88

16. Whole-Molecule Scoring Advantages • Produces more diverse, non-obvious bioisosteres • Avoids fragment scoring limitations • Allows for electronic influence of replacing a moiety on the rest of the molecule and vice versa • Allows for neighbouring group effects

17. Example - COX-2 • Search for Bioisosteres for cyclic lactone of Rofecoxib Search Common Dbs Actives: 9 of the first 10 clusters 21 of the first 30 clusters 87,225 frags

18. COX-2 Results

19. Scaffold replacement ‘Sildanafil’ NEAT? spark (10 mins) Pfizer J. Chem. Inf. Model. 2012

20. Fragment growing example • FieldStere version 3.0.0 fragment growth example: • P38 kinase bound to a fragment fluorescent probe PDB:3K3I specific to the ‘DFG-out’ conformation • ‘DFG-in’ example with specificity towards the ‘Gly’ flipped hinge PDB:3ROC and/or 3HUB • Selectivity potentially to be gained by combining ‘Gly flip’ and ‘DFG-out’ in one molecule • Can we use the new version of SparkV10 to grow the DFG-out fragment into the DFG-in hinge?

21. Fragment in DFG-out pocket, PDB:3K3I predominant hinge conformation Graphics from Pymol from Delano Scientific

22. +Gly hinge flip ligand_1, PDB:3ROC Hinge Gly flip Graphics from Pymol from Delano Scientific

23. Fragment compatibility – DFG-out

24. Fieldstere output: 2D mols

25. Fieldstere output: 3D mols and fields Fragment and reference Rank 4 Rank 6 Rank 11 Rank 13 Rank 53

26. Outcome • Fragment growth both possible and a facile using an automated process with SparkV10 • Interesting and sensible candidate molecules generated • Predict highly selective p38 actives • Absolute requirement for 3D insight

27. Any relevance? – Pfizer compound for COPD Deposited in PDB: 2YIS November 2011 Clinical trials for COPD Virtual compounds in the output list……prepared for ACS San Diego Late Summer 2011

28. Conclusion • Cresset offer a wide variety of software and collaborative solutions for drug discovery • Cutting edge technology • Provide key insights

29. martin@cresset-group.com Questions welcomed