1. 1 Szabolcs Csepregi May, 2005 Structural Search Using ChemAxon Tools

2. Slide 2 Structural Search Using ChemAxon Tools May 2005 2 Structural Search Using ChemAxon Tools Search types in JChem Interfaces Search options Search query features Stereo searching The Chemical Terms language Performance Applications of structural search: R-group decomposition Standardizer, Reactor, Pmapper, Fragmenter Future plans All examples were generated by Marvin

3. Slide 3 Structural Search Using ChemAxon Tools May 2005 3 Search types in JChem Atom By Atom Search or structural search: Similarity search: – Different Descriptors – Different Metrics MC(E)S – maximum common (edge) substructure Perfect Exact Superstructure Substructure ResultQueryStructural search type

4. Slide 4 Structural Search Using ChemAxon Tools May 2005 4 Structural search interfaces JSP( Java Server Pages ): web GUI for database Command line utility: jcsearch: for files and DB Java API: –MolSearch class isMatching() – Only to check matching findFirst(), findNext()Enumerate all findAll() possible matchings –JChemSearch class: JChem Base Cartridge: access all functionality from SQL Chemical Terms

5. Slide 5 Structural Search Using ChemAxon Tools May 2005 5 ABAS options Structural search options: Order sensitive hits e.g. Pre-assignment of query and target atoms Consider stereo or not, absolute stereo (ignore chiral flag) Timeout limit Exact charge/radical/isotope/query features/bond/stereo matching Double bond stereo: no check/marked/all double bonds Chemical Terms filter expression etc

6. Slide 6 Structural Search Using ChemAxon Tools May 2005 6 Query features 1. Atomic features Query atom types: any, hetero, list, not list Pseudo atoms e.g. Resin Explicit lone pairs (matches to implied lone pairs as well.) Charge, isotope, radical

7. Slide 7 Structural Search Using ChemAxon Tools May 2005 7 Query features 2. Query properties Query properties: Coming soon in search (Can be drawn in Marvin already): Ring bond count: rb, rb* Substitution count: s, s* Unsaturated atom: u SymbolDescription H Total hydrogen count aAromatic AAliphatic R Ring count in SSSR r Ring size in SSSR v Valence X Connectivity D Degree h Implicit H count

8. Slide 8 Structural Search Using ChemAxon Tools May 2005 8 Query features 3. Atomic SMARTS features SMARTS atoms: Additional query properties: Example: Carbonyl C, but not amide SymbolDescription & ;, !Logical operators $( )Recursive smarts +0, -0Zero charge

9. Slide 9 Structural Search Using ChemAxon Tools May 2005 9 Query features 4. 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 SymbolDescription - = #Single, double, triple :aromatic &, ; !Logical operators @Ring bond / \ /? \?Directional bond (cis/trans) SymbolDescription (C.C)Same component (C).(C)Different component C.CNo component restrictions

10. Slide 10 Structural Search Using ChemAxon Tools May 2005 10 Stereo searching 1. Double bonds Levels of check: –All –Only marked double bonds (MDL: stereo care flag) –None Not cis Not trans Cis or trans (unknown) Trans Cis MeaningDepiction

11. Slide 11 Structural Search Using ChemAxon Tools May 2005 11 Stereo searching 2. Tetrahedral chirality Stereo bond types: Relative stereo configuration Chiral flag model Enhanced stereo representation: AND, OR, ABS groups Up or downDownUp

12. Slide 12 Structural Search Using ChemAxon Tools May 2005 12 S-group integration (query & target) Both sides are treated similarly by the search: Abbreviations (super-atom S-groups): Multiple groups:

13. Slide 13 Structural Search Using ChemAxon Tools May 2005 13 Reaction search Reactants, agents, products Transformation recognition (mapping) Stereospecific reactions (inversion, retention) Reactant grouping

14. Slide 14 Structural Search Using ChemAxon Tools May 2005 14 R-group search Scaffold, R-group definitions Monovalent, divalent R-groups R-logic Occurrence If-then Rest H

15. Slide 15 Structural Search Using ChemAxon Tools May 2005 15 Hydrogens H representations: – Explicit – Implicit – Query H count: – total (H ) – implicit (h ) Example: Considered in ABAS Explicit HImplicit HQuery H count Query Target Query

16. Slide 16 Structural Search Using ChemAxon Tools May 2005 16 Applications of Chemical Terms CT virtual synthesis reaction and synthesis rules pharmacophore analysis pharmacophore definitions drug design goal functions structural search advanced query expressions e.g. in the Cartridge

17. Slide 17 Structural Search Using ChemAxon Tools May 2005 17 Chemical Terms searching match("olefine.mol") && !match("c1ccncc1") && (atomCount(16) == 0) || (mass() < 300); goal functions inhibitor = inhibitor.mol; (similarity(inhibitor, pharmacophore_tanimoto) > 0.8) && (similarity(inhibitor, chemical_tanimoto) < 0.5); filtering (mass() <= 500) && (logP() <= 5) && (donorCount() <= 5) && (acceptorCount() <= 10); structure matching functions (describing functional groups, reaction sites, similarity…) property calculations (partial charge distribution, pKa, logP, HB donors, acceptors, …, etc) arithmetic and logic-operators Elements of the language Chemical Terms examples

18. Slide 18 Structural Search Using ChemAxon Tools May 2005 18 Chemical Terms Some available functions Structural search (match, matchcount) Partial charge distribution pKa, Log P, Log D, major microspecies Polarizability Topological Polar Surface Area Number of rotatable bonds, rings, aromatic rings, etc. Number of HB donors/acceptors Exact mass Arithmetic and logic operators Extensible: your own Java plugins can be easily added. Etc.

19. Slide 19 Structural Search Using ChemAxon Tools May 2005 19 Performance Searching a file containing 100,000 smiles structures from NCI 99 with the jcsearch command-line application (JChem 3.0.9, P4 2.6GHz, 768M RAM) QueryHits Search Time (s) Total (elapsed, including IO & aromatization) Search only (measured from API) 124.20.6 4626.71.8 45,82165.65.4 CCOC(=O)C1=CN=C2C(C)=C(Cl)C=CC2=C1O NC1=CC2=C(C=C1)C(=O)C3=C(C=CC=C3)C2=O CC1=CC=CC=C1

20. Slide 20 Structural Search Using ChemAxon Tools May 2005 20 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

21. Slide 21 Structural Search Using ChemAxon Tools May 2005 21 Further applications of structural search in JChem Transformations - Standardizer & Reactor Identification of pharmacophoric groups - Pmapper nitro:amidine: Identification of bond cleavage - Fragmenter ether cut: Enamine-amine tautomerism: Converting covalent form of alcoholates to ionic form:

22. Slide 22 Structural Search Using ChemAxon Tools May 2005 22 Future plans More query features (e.g link nodes, ring bond count, substitution count, unsaturated atom) Flexible search options: tautomeric search, ignore bond types, salts, etc. Search targets having R-groups (Markush structures) etc.

23. Slide 23 Structural Search Using ChemAxon Tools May 2005 23 Summary JChem suite: contains a broad range of chemical search facilities. Chemical Terms: allows easy and flexible data mining. Structural search is a useful tool for many applications.

24. Slide 24 Structural Search Using ChemAxon Tools May 2005 24 References JChem Query Guide: http://www.jchem.com/doc/user/Query.html Chemical Terms reference: http://www.jchem.com/doc/user/EvaluatorLanguage.html JChem Base JSP demo page: http://www.jchem.com/examples/jsp1_x/index.jsp Jcsearch command line tool: http://www.jchem.com/doc/user/Jcsearch.html API documentation: http://www.jchem.com/doc/api/index.html http://www.jchem.com/doc/api/index.html (chemaxon.sss.search.MolSearch, chemaxon.jchem.db.JChemSearch)chemaxon.sss.search.MolSearchchemaxon.jchem.db.JChemSearch

25. Slide 25 Structural Search Using ChemAxon Tools May 2005 25 Máramaros köz 3/a Budapest, 1037 Hungary info@chemaxon.com www.chemaxon.com Thank you for your attention