ChemAxon in 3D

1. ChemAxon in 3D Gábor Imre, Adrián Kalászi and Miklós Vargyas Solutions for Cheminformatics

2. Talk overview • ChemAxon’s 2D tradition • visualize • depict/edit • search • calculate/predict properties • 3D pearls

3. 3D visualization

4. 3D structure generation

5. 3D search And what do we do with 3D structures? Like what, why, give motivation Perhaps we can show some cars without going to details, just en passant But we may refer to shapes

6. Advanced 3D visualization

7. 3D structure generation Why is 3D structure generation hard What are the typical approaches

8. Our approach Chemically aware coordinate and conformer generation Reliable, robust

9. Searching in 3D • Molecules are inherently spatial objects • Typical searches are two-dimensional • Molecular descriptor • Fingerprint

10. 3D alignment

11. Conformational flexibility

12. Multi-conformer rigid search • One viable solution to tackle conformational flexibility • The rigid apparatus can be applied • Highly combinatorial: • All target conformation need to be considered • Do we have multiple query conformations? • multiple conformations have to be generated

13. Multiple conformation generation • Molecular mechanics based geometry optimization • Improved Dreiding force field to suite wider range of (small organic) molecules • Modified to support efficient optimization • Fast numeric optimization

14. 3D alignment Minimizes atom-pair distance constraints

15. Alignment of challenging molecules

16. 3D shape similarity T= - +

17. 3D virtual screening 3D flexible virtual screening on 2D molecules with 2D query Maximizes colored shape intersection of the query and the target Calculates volume Tanimoto of the optimum 3D flexible alignment

18. 3D pharmacophore fingerprint

19. 3D pharmacophore fingerprint

20. Summary • 3D molecule alignment • Rigid – all conformations are intact • Flexible – all conformations may change • Combined – only the selected molecules are rigid, the others treated flexible • Atom pairing • User defined • Auto align – tries to find the optimal overlay • Combined • Chemically sound conformations • Optional ring flexibility

21. Summary • 3D virtual screening • Minimal and maximal interatomic distances are calculated between atoms of given types • The costly calculation of the fingerprint is done only once per library • The similarity search is as fast as with 2D fingerprint • All the popular similarity functions can be calculated: Tanimoto, Tversky, Dice, Euclidean.

22. MD • Simple dreiding based MD • Used internally by hyperfine • Available as a plugin also • Projected MD • In development • Rigid term energy redistribution • Extremely fast conformational transitions due to the elimination of vibrational components

23. 3D calculations • Conformers plugin • Coordinate / conformers generation • Geometry optimization • Energy calculation • Geometry plugins • Steric hindrance • Molecular surface area • Molecular projection area • Molecular volume

24. Acknowledgement Dr. Ödön Farkas Dr. Imre Jákli Judit Vasko-Szedlar