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

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

3. M. Wagener 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. Receptor Ligand

4. M. Wagener 3D Database Searching Docking Using the lock, find keys that fit Pharmacophore Search Look for keys with same features

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

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

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

8. M. Wagener Fragmentation into Cyclic/Acyclic Parts

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

10. M. Wagener Joining of Ring Templates: Cubane Ring 2Ring 3Ring 4Ring 5 no conformation for 3rd ring Ring 1

11. M. Wagener Joining the Fragments

12. M. Wagener Conformational Flexibility conformational ensemble low-energy conformation

13. M. Wagener Conformational Analysis Systematic Search –high number of conformers: e.g. 10 rotatable bonds with 120º steps: 3 10 ~ 60,000 conformers Sampling Techniques –Molecular Dynamics, Distance Geometry, Simulated Annealing Poling: Promoting Conformational Variation

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

15. M. Wagener Conformational Poling A. Smellie, S.L. Teig, P. Towbin J. Comp. Chem. 1995, 16, 171. Conformational Coordinate Energy +E pole Energy = E bond +E angle +E dihedral +E nonbonding C3C2 C1

16. M. Wagener 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 Receptor Ligand

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

18. M. Wagener 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 2 - 3 Å 4 - 7.2 Å 6 - 8 Å adapted from: C.D. Strader et al. J. Biol. Chem. 1989, 264, 13572.

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

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

21. M. Wagener Alignment of 2 Search Hits

22. M. Wagener Quality of the Pharmacophore Adrenergic agonists: Hits active / Hits total DB active / DB total EF == 7.0 49 / 843 119 / 14251 = Hits active / Hits total DB active / DB total EF == 4.3 41 / 843 162 / 14251 = Dopaminic Agonists:

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

24. M. Wagener Conventional Approaches Similarity Search uses overall similarity to retrieve structures Pharmacophore Search focuses on features important for receptor-ligand interaction

25. M. Wagener Scaffold Hopping Goal Find similar scaffolds, not similar compounds Approach 1)Generate a non-redundant database of scaffolds 2) Store position and orientation of substitution sites 3) Use orientation of substitution sites on the query to identify new scaffolds Example Estrogen antagonists

26. M. Wagener Generating the Scaffolds Database ACDOrganonDrugsScaffolds scaffold extraction canonization conformational analysis

27. M. Wagener Scaffold Extraction ringsystem scaffold π-scaffold

28. M. Wagener Searching the Database 3D query Scaffolds suggested scaffolds

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

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

31. M. Wagener Results: Matching the Query LY-357489

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

33. M. Wagener Conclusions 3D Database Searching as valuable tool for virtual screening 2D-to-3D Conversion based on an automated assembly of fragments Conformational Analysis to take into account molecular flexibility Pharmacophores comprise features essential for biological activity Scaffold Hopping focuses on similar spatial orientation of substituents

34. M. Wagener 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. Today 1996, 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.