1. August 2010, ACS National meeting, Boston Representation of Markush structures from molecules towards patents Szabolcs Csepregi Solutions for Cheminformatics

2. August 2010, ACS National meeting, Boston Contents ChemAxon What are Markush structures? How to get them? What can be done with them? –Enumeration –Storage, search Challenges in chemical representation Under development

3. August 2010, ACS National meeting, Boston ChemAxon Cheminformatics toolkits and applications HQ: Budapest, Hungary Founded: 1998 Main customers: pharma, biotech, publishing 3rd party applications and web sites. (e.g. Integrity, Reaxis, PDB ligand search, ELN-s, registration systems, etc)

4. August 2010, ACS National meeting, Boston ChemAxon Main products: –Structure drawing & visualization (Marvin family) –Chemical DB tools (JChem family) –Property predictions (Calculator plugins) –Drug discovery tools (Reactor, JKlustor, etc.) Development strategy: customer-driven

5. August 2010, ACS National meeting, Boston What are Markush structures and how to get them?

6. August 2010, ACS National meeting, Boston Markush structures Generic notation for describing many molecules (= Markush library) in a compact form. Main usage: –Combinatorial chemistry –Chemistry-related patents

7. August 2010, ACS National meeting, Boston Markush structures Current features handled: –R-groups –Atom lists, bond lists –Position variation bond –Link nodes –Repeating units –Homology groups (aryl, alkyl, etc.)

8. August 2010, ACS National meeting, Boston ChemAxon Markush project Goals: –Extend structural search capabilities to combinatorial Markush structures –Markush enumeration Complications: –Practical examples may be very complex, methods using explicit enumeration may be impossible –Extension of current molecular formats (generic features) Timeline –Pilot study started in 2005 Q4, –First prototype shown at UGM, 2006 June –Released in JChem 5.0, 2008 –Markush DARC format support 5.3.0 2010

9. August 2010, ACS National meeting, Boston How to get Markush structures? Drawing – Marvin Sketch

10. August 2010, ACS National meeting, Boston How to get Markush structures? Patent literature – Markush DARC format (*.vmn) Compatible with Thomson Reuters MMS patent Markush database (Test set available.)

11. August 2010, ACS National meeting, Boston How to get Markush structures? Combinatorial chemistry – Reagent clipping 1.Replace reacting group with attachment point (Reactor tool) 2.Turn fragments to R-group definitions (Molconvert tool) 3.Add a scaffold (Molconvert tool)

12. August 2010, ACS National meeting, Boston How to get Markush structures? Combinatorial chemistry – R-group decomposition 1.Filter and identify ligands in chemical library 2.Create Markush structure from R-table (R-group decomposition tool)

13. August 2010, ACS National meeting, Boston What to do with them?

14. August 2010, ACS National meeting, Boston Markush Enumeration Markush enumeration plugin –Full enumeration –Selected parts only –Random enumeration –Calculate library size –Scaffold alignment and coloring –Markush code –Optional example homology group enumeration

15. August 2010, ACS National meeting, Boston Markush storage & search JChem Base and Instant JChem No enumeration involved Can handle complex Markush structures (10 40 or more) Substructure and Full structure search Broad translation of homology groups is supported. (Homology in DB, specific in query.)

16. August 2010, ACS National meeting, Boston Markush storage & search Substructure hit visualization Query Result in original Markush

17. August 2010, ACS National meeting, Boston Markush storage & search Substructure hit visualization: Markush structure reduction Query Result in original Markush Reduced result

18. August 2010, ACS National meeting, Boston Main use cases Patent search hits refining / visualization, White space analysis, Patent busting, Markush structure curation, In-house storage of small Markush DB, etc...

19. August 2010, ACS National meeting, Boston MMS evaluation Instant JChem project

20. August 2010, ACS National meeting, Boston Challenges in chemical representation (solved)

21. August 2010, ACS National meeting, Boston Representation - What we already had Generic notation in queries: Atom lists, bond lists R-group queries (Problem: RGFile R-logic and patent R-logic are different! - Solution: Just ignore R-logic.) Link nodes Some generic atoms (X) – represented as pseudo atoms. Single or double

22. August 2010, ACS National meeting, Boston Challenge 1: Attachment point Multiple – ligand order and attachment order Heavily used in Markush DARC (up to 8 attachments!) Represented as atom property Parent group (root) R-group definitions Order of ligands for G15 (R15) Attachment points for definitions

23. August 2010, ACS National meeting, Boston Challenge 1: Attachment point Embedded R-groups: Grandparent relations may be needed between attachment points: G3s attachment point 1 is mapped to G4s attachment point 1

24. August 2010, ACS National meeting, Boston Challenge 1: Attachment point Temporary representation: attached data –ligand order –attachment point in R-group definition –still an atom property –ligand order sometimes in parent group (grandparent relation) Order of ligands for R2 Attachment points for definitions

25. August 2010, ACS National meeting, Boston Challenge 1: Attachment point Real attachment object with bond (under development) –eliminates need for grandparent relations table: Order of ligands for R4 Attachment point for R3 Order of ligands for R2 Attachment points for definitions

26. August 2010, ACS National meeting, Boston Challenge 2: Abbreviations Superatom S-groups were originally in Marvin (~700 built-in shortcuts) –Expand / Contract –Search code already handled them in specific structures. M. DARC had 21 shortcuts + 31 peptides. Attachment point next to abbreviations –Needed to be visible outside and handled correctly inside. –New attachment point solves this also:

27. August 2010, ACS National meeting, Boston Challenge 3: Homology groups (generics) Pseudoatom representation Naming (Still looking for the most descriptive long names.) Extra conditions: general atom property framework (under development) Markush DARC nameLong name CHKalkyl CYCcarboAlicyclyl ARYcarboAryl HEAheteroMonoAryl

28. August 2010, ACS National meeting, Boston Challenge 4: Frequency variation Link nodes Repeating units: modified SRU Multipliers: –special SRU, 1 outer bonds. –(Currently visualization only.) Moieties: –special SRU, 0 outer bonds –to describe (variable) stoichiometry –(Currently visualization only.)

29. August 2010, ACS National meeting, Boston Challenge 5: Position variation bond New special S-group type Relocatable multicenter atom represents group for bonds Also useful to represent multicenter charge and coordination compounds:

30. August 2010, ACS National meeting, Boston What (else) keep us busy

31. August 2010, ACS National meeting, Boston Under development Further improvements in Markush DARC support: –Ring segment groups (XX form a ring) –New, more robust representation for attachment points –Homology properties (low alkyl, fused aryl, C1-3, N2-5, etc) Ranking of results New ways to navigate/zoom Markush structures Maximum common substructure search Biased enumeration and covering Markush – based on examples in patent. Improve search speed to handle larger Markush sets. Other Markush formats – Markush InChI standard committee Overlap analysis of Markush structures Conditions for Markush variables

32. August 2010, ACS National meeting, Boston Summary Markush structure storage, search and enumeration at ChemAxon now patent coverage Compatible patent data is available from Thomson Reuters Well thought out chemical representation Continuous development, improvements in the pipeline

33. August 2010, ACS National meeting, Boston Acknowledgements Development team: Nóra Máté, Róbert Wágner, Szilárd Dóránt, Tamás Csizmazia, Tim Dudgeon, Erika Bíró, Ali Baharev, Ferenc Csizmadia, et al. Tim Miller, Steve Hajkowski, Gez Cross and Linda Clark at Thomson Reuters for useful discussions, help and example Markush DARC files Many early adopters and colleagues within the field for suggestions and feedback