Combinatorial Markush structure handling at ChemAxon: US UGM 2008


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Markush structure handling at ChemAxon range of products will be presented, including drawing, visualization and generation of Markush structures, Markush enumeration techniques and searching. It will be shown how libraries more complex than 10^30 library size are handled, with the generic description including R-groups, atom and bond lists, link nodes and position variation. Further developments towards patent Markush structure handling will be also discussed.
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Combinatorial Markush structure handling at ChemAxon: US UGM 2008

  1. 1. Combinatorial Markush structures at ChemAxon: from drawing to analysis Szabolcs Csepregi Solutions for Cheminformatics
  2. 2. Outline • Combinatorial and patent Markush structures • Drawing Combinatorial Markush structures with Marvin • Markush Enumeration • Markush registration & searching in a database • What is coming in Marvin / JChem 5.1 • Future plans – towards patents 2
  3. 3. Markush structures Generic notation for describing many molecules (= Markush library) in a compact form. Main usage: – Combinatorial chemistry: similar steps of synthesis – Chemistry-related patents: to claim part of the chemical space for a particular purpose. 3
  4. 4. Markush structures Combinatorial Markush Patent Markush • Smaller libraries • The goal is as wide • Usually simpler coverage as possible constructs: • Uses more – R-groups sophisticated methods – Link nodes – Homology variation – Atom lists (Alkyl, Aryl, etc.) – Position variation • Suitable to describe – Etc. simpler patents • Extra conditions to avoid overlap with existing patents 4
  5. 5. Drawing with Marvin • Easy R-group drawing & zoom functions • Atom list, link node, bond list • Position variation New in 5.1 5
  6. 6. Enumeration • Full enumeration • Selected parts only • Random enumeration • Calculate library size exact size of huge Markush libraries – arbitrary precision or – magnitude 6
  7. 7. Enumeration • Coloring: scaffold and each R-group parts get different colors New in 5.1 • Alignment: as original scaffold 7
  8. 8. Markush database tables • Available in JChem Base and Instant JChem • Search in the Markush library space of combinatorial Markush structures – No enumeration involved – can handle very complex Markush structures (tested up to 1040, but no explicit limits were built in.) – Search types: • Substructure • Exact structure (contained in the Markush library) • Exact fragment • Perfect (same Markush structure) – Stereochemistry, query atoms, bonds, query properties: • Aromatic/aliphatic atom, ring atom and bond, chain bond, number of bonds handled 8
  9. 9. Markush database tables Markush structure reduction to display substructure hits: All matchings of the query to the Markush structure are reduced into less generic structures. (Generic parts overlapping the hit are expanded.) Example Markush structure Reduced Markush structures with hit coloring + Query 9
  10. 10. Integration in Instant JChem 2.3 New in 2.3 • Markush tables available: create, import, insert, search • Show / hide R-groups for Markush table views • Markush enumeration / hit reduction dialog 10
  11. 11. What is coming in 5.1 New in 5.1 • Drawing – Easier sketching of position variation (from 5.0.2) • Markush features – Position variation • Enumeration: – R-group coloring – Scaffold alignment • Markush search: – Abbreviations (superatom s-groups) can be included in Markush structures (from 5.0.2) – Position variation in both query and database 11
  12. 12. Longer term plans Further developments towards patents • Homology variation (Alkyl, Aryl, Protecting group, etc.) – properties (# of atoms, branching points, # of heteroatoms, etc.) • Multiple graphical attachment points for R-groups • Larger repeating groups • Bridged definition of multiple R-atoms R1, R2= H, CH3, NO2 or together form a ring 12
  13. 13. Thank you for your attention! For more information please visit 13