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Structural Search Using ChemAxon Tools

Structural Search Using ChemAxon Tools. Szabolcs Csepregi. JChem version 5.3, April 2010. Structural Search Using ChemAxon Tools. Interfaces Search types and options Query features , Stereo searching Special search types: reaction, R-group search, Chemical Terms filters

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Structural Search Using ChemAxon Tools

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  1. Structural Search Using ChemAxon Tools Szabolcs Csepregi JChem version 5.3, April 2010

  2. Structural Search Using ChemAxon Tools Interfaces Search types and options Query features, Stereo searching Special search types: reaction, R-group search, Chemical Terms filters Searching against Combinatorial Markush structures Fingerprint screening Performance Applications of structural search:R-group decomposition, Standardizer,Reactor, Pmapper, Fragmenter Future plans All examples were generated by Marvin

  3. Structural search interfaces • Example web GUI-s: • JSP(Java Server Pages) • AJAX example: Javascript and JChem Web Services • Command line: jcsearch • Java and .NET API: • MolSearchclass:in memory • JChemSearch class:in database • Cartridge: Oracle SQL • JChem Web Services • Instant JChem • JChem For Excel

  4. Search types in JChem Structural search type Query Result • Atom By Atom Search or structural search: • Similarity search: • Different Descriptors • Different Metrics Substructure Superstructure Full structure Duplicate MC(E)S– maximum common (edge) substructure

  5. Some selected structure search options: Stereo on/off/diastereomers Ignore charge/isotope/radical/valence/polymers, etc. Vague bond matching options Chemical Terms filter Tautomer search (even in substructure search) Inverse hit list Maximum search time / number of hits Combine with non-structure conditions Ordering of results Similarity type / metric Search options 5

  6. Hit coloring and alignment

  7. Query features 1. Atomic features • Query atom types: • any(A, AH) • hetero (Q, QH) • list, not list • metal (M, MH) • halogen (X, XH) • periodic table groups (G1-18) • Pseudo atoms e.g. “Resin” • Explicit lone pairs (match to impliedlonepairs as well.) • Charge, isotope, radical • Link nodes (repeatable):

  8. Query features 2. Query properties

  9. Query features 3. Atomic SMARTS features • SMARTS atoms: • Additional query properties: • Example: • Carbonyl C, but not amide

  10. Query features 4. Homology atoms • Can be used: • In queries against molecule and reaction tables. • In Markush structures • Built-in and user-defined groups

  11. Query features 5. Bond features & components • Query bond types: Any, single or double, single or aromatic, double or aromatic • Bond topology: chain/ring • Smarts bonds • Component level grouping

  12. Coordination compounds Atom-to-atom (dative) and multicenter coordinate bonds.Alternative representations: Position variation bond

  13. Hydrogens • H representations: • Explicit • Implicit • Query H count: • total (H<n>) • implicit (h<n>) • Example:

  14. Depiction Meaning Cis Trans Cis or trans (unknown) Not trans Not cis Stereo searching 1. Double bonds • Levels of check: • All • Only marked double bonds (MDL: stereo care flag) • None

  15. Up Down Up or down Stereo searching 2. Tetrahedral chirality • Stereo bond types: • Relative stereo configuration • Chiral flag model • Enhanced stereo representation: AND<n>, OR<n>, ABS groups

  16. Groups integration (query & target) Both sides are treated similarly by the search: • Abbreviations (super-atom S-groups): • Multiple groups: Other S-groups supported: component, mixture, formulation , many polymer brackets:

  17. Reaction search • Reactants, agents, products • Transformation recognition (mapping) • Stereospecific reactions (inversion, retention) • Reactant grouping • Reacting center

  18. R-group search • Scaffold, R-group definitions • Monovalent, divalent R-groups • R-logic • Occurrence • If-then • Rest H

  19. Undefined R-atoms - No substitution elsewhere retrieves:

  20. Polymer storage and search • Comprehensive representation • Source based and structure based • Copolymer types, mixtures, ladder-type polymers, etc • Phase shifting • End groups: specific, undefined, etc. • Flexible • Attached data search • Wide range of polymer search options

  21. Chemical Terms filter • Chemically aware filtering for structure and similarity searches • Elements of the Chemical Terms language • structure matching functions (describing functional groups, reaction sites, similarity, etc) • property calculations (partial charge distribution, pKa, logP, HB donors, acceptors, topological descriptors, etc) • arithmetic and logic-operators • Examples

  22. Markush structures • Markush structure registration and search • Markush features • R-groups • Atom lists, bond lists • Position variation bond • Link nodes and repeating units • Homology groups • Compatible enumeration plugin

  23. query JChem table Search Fingerprintscreening Hits for the query Screenedout Need to be searched Atom by atom search Results Fingerprint screening in the database • JChem database searches use fingerprint technology for fastest search results. • It rapidly* filters out most non-hits -usually more than 99% of them are rejected. • Supported fingerprint types: • Chemical hashed fingerprints • User-defined additional structural keys * Average screening time in a 3-million cached table: ~0.1s

  24. Application: R-group decomposition JChem is able to identify the ligands of a given scaffold at specified substitution positions: Query(scaffold) Result Library R-group decomposition

  25. Further applications of structural search in JChem • Transformations - Standardizer & Reactor • Identification of pharmacophoric groups - Pmappernitro:amidine: • Identification of bond cleavage - Fragmenter ether cut: Enamine-amine tautomerism: Converting covalent form of alcoholates to ionic form:

  26. Performance Substructure searching in 19.5 million structures (Pubchem) JChem Base 5.2.2, Intel Quad Q6600 2.4GHz, 8 GB RAM; Oracle 10.2.0.3 Compound registration:

  27. Future plans • R-group decomposition GUI in client applications • Visualization of similarity search results using MCS • Diastereomer search • Markush search enhancements (homology variation conditions, maximum common substructure, etc)

  28. Summary • JChem suite: contains a broad range of chemical search facilities, including Markush structure analysis. • Structural search is a useful tool for many applications.

  29. References • JChem Query Guidehttp://www.chemaxon.com/jchem/doc/user/Query.html • Chemical Terms referencehttp://www.chemaxon.com/jchem/marvin/help/chemicalterms/ChemicalTerms.html • JChem Base JSP demo pagehttp://www.chemaxon.com/jchem/examples/db_search/index.jsp • Jcsearch command line toolhttp://www.chemaxon.com/jchem/doc/user/Jcsearch.html • API documentationhttp://www.chemaxon.com/jchem/doc/api/index.html • (chemaxon.sss.search.MolSearch, chemaxon.jchem.db.JChemSearch) • JChem Base http://www.chemaxon.com/product/jc_base.html • JChem Cartridge http://www.chemaxon.com/product/jc_cart.html • Instant JChem http://www.chemaxon.com/product/ijc.html • JChem for Excel http://www.chemaxon.com/products/jchem-for-excel/

  30. Thank you for your attention Máramaros köz 3/a Budapest, 1037Hungaryinfo@chemaxon.comwww.chemaxon.com

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