3D Database Searching and Scaffold Hopping

1. 3D Database Searching and Scaffold Hopping Markus Wagener NV Organon

2. Database Searching • Selection of compounds for testing • Generation of new ideas • Validation of proposed structural requirements for activity

3. Lock-and-Key Principle ‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’Emil Fischer, Ber. Dtsch. Chem. Ges.1894, 27, 2985. Ligand Receptor

4. 3D Database Searching DockingUsing the lock, find keys that fit Pharmacophore SearchLook for keys with same features

5. Outline • Database Building • 2D-to-3D Conversion • Multi-Conformational Databases • Pharmacophoric Searches • Scaffold Databases • Scaffold Hopping

6. Available Compound Collections Size x 1000 http://cactus.nci.nih.gov/ncidb2/

7. 2D-to-3D Conversion: Corina J. Sadowski, J. Gasteiger Chem. Rev.1993, 93, 2567.

8. Fragmentation into Cyclic/Acyclic Parts

9. Ring Templates 27 kJ/Mol 18 kJ/Mol 50 kJ/Mol 25 kJ/Mol 56 kJ/Mol 43 kJ/Mol

10. no conformationfor 3rd ring Ring 1 Ring 2 Ring 3 Ring 4 Ring 5 Joining of Ring Templates: Cubane

11. Joining the Fragments

12. Conformational Flexibility low-energyconformation conformationalensemble

13. Conformational Analysis • Systematic Search • high number of conformers:e.g. 10 rotatable bonds with 120º steps: 310 ~ 60,000 conformers • Sampling Techniques • Molecular Dynamics, Distance Geometry, Simulated Annealing • Poling: Promoting Conformational Variation

14. Conformational Flexibility Energy [kJ/Mol] Torsion Angle

15. Energy = Ebond + Eangle Energy C3 C2 C1 + Edihedral + Enonbonding Conformational Coordinate Conformational Poling + Epole A. Smellie, S.L. Teig, P. Towbin J. Comp. Chem.1995, 16, 171.

16. Lock-and-Key Principle ‘‘. . . the intimate contact between the molecules . . . is possible only with similar geometrical configurations. To use a picture, I would say that the enzyme and the substrate must fit together like a lock and key.’’ Emil Fischer, 1891 Ligand Receptor

17. Protein-Ligand Interaction • hydrogen bonds • salt bridges • hydrophobe interactions • cation-π interactions • metal complexes

18. 6 - 8 Å 2 - 3 Å 4 - 7.2 Å Pharmacophore Definition A pharmacophore is a specific spatial arrangement of atoms or functional groups required for a drug molecule to exert a particular biological effect. adrenaline adapted from: C.D. Strader et al.J. Biol. Chem.1989, 264, 13572.

19. Pharmacophore Elements Hydrogen bond donors: Hydrogen bond acceptors: Hydrophobes: Positive ionizable groups: Negative ionizable groups:

20. 6 - 8 Å 2 - 3 Å 4 - 7.2 Å 3DDatabase Pharmacophore Searching 7 CPU min 14251druglike compounds 843search hits

21. Alignment of 2 Search Hits

22. Hitsactive / Hitstotal Hitsactive / Hitstotal EF = EF = = = = 7.0 = 4.3 DBactive / DBtotal DBactive / DBtotal 41 / 843 49 / 843 • Dopaminic Agonists: 119 / 14251 162 / 14251 Quality of the Pharmacophore • Adrenergic agonists:

23. New Scaffold Scaffold Hopping Breaking out of old series: • no further optimization possible • patent issues • backup

24. Conventional Approaches Similarity Searchuses overall similarity to retrieve structures Pharmacophore Searchfocuses on features important for receptor-ligand interaction

25. Scaffold Hopping GoalFind similar scaffolds, not similar compounds Approach1) Generate a non-redundant database of scaffolds2) Store position and orientation of substitution sites3) Use orientation of substitution sites on the query to identify new scaffolds ExampleEstrogen antagonists

26. Scaffolds Organon Drugs ACD Generating the Scaffolds Database scaffoldextraction canonization conformational analysis

27. Scaffold Extraction ringsystem scaffold π-scaffold

28. 3D query Scaffolds Searching the Database suggestedscaffolds

29. substitution sites + aromatic ring + ring orientation + directions + shape 3D query raloxifene A Query for ER antagonists

30. Scaffolds Hits with the ER Antagonist Query 1027 hits 631 π-scaffolds 364 scaffolds 261 ringsystems 3D query

31. LY-357489 Results: Matching the Query

32. raloxifene arzoxifene LY-357489 EM-652 LY-335124 RU-39411 pipendoxifene LY-326315 Other Scaffolds ...

33. Conclusions 3D Database Searchingas valuable tool for virtual screening 2D-to-3D Conversion based on an automated assembly of fragments Conformational Analysisto take into account molecular flexibility Pharmacophorescomprise features essential for biological activity Scaffold Hoppingfocuses on similar spatial orientation of substituents

34. Further Reading • A.C. Good, J.S. Mason Three-Dimensional Structure Database Searches. in: Reviews in Computational Chemistry, K.B. Lipkowitz, D.B. Boyd, Ed., VCH Publishers, 1996, 67-117. • D.T. Manallack Getting that Hit: 3D Database Searching in Drug Discovery. Drug Disc. Today1996, 1, 231-238. • M.A. Miller Chemical Database Techniques in Drug Discovery. Nat. Rev. Drug Disc.2002, 1, 220-227. • H.J. Böhm, G. Klebe, H. Kubinyi Wirkstoffdesign. Spektrum Verlag, 1996. available only in German, but really worth the effort.