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SimFinder : A Unique Topology -based Approach to Similarity Searching

SimFinder : A Unique Topology -based Approach to Similarity Searching. SimFinder. Topology-based similarity search Flexibility Parameterized similarity measure User-defined functional group abstractions Scalability using index structure

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SimFinder : A Unique Topology -based Approach to Similarity Searching

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  1. SimFinder: A Unique Topology-based Approach to Similarity Searching

  2. SimFinder • Topology-based similarity search • Flexibility • Parameterized similarity measure • User-defined functional group abstractions • Scalability using index structure • One-to-many comparisons at a time between query compound and database compounds • Alternative techniques rely on one-to-one comparisons

  3. Applications of SimFinder • Better diversity analysis of databases • Topology reveals unique insights • Functional group abstractions • User-directed • User can define graph attributes (e.g., types of covalent & non-covalent bonds). • Ligand-protein interactions can be defined & queried.

  4. Key Benefits Flexibility Intuitiveness MCS Scalability SimFInder ECFP, FCFP Only technology offering flexibility, intuitive searches, and scalability Unity & Daylight fingerprints, MACCS

  5. 49 5HT3 Re-uptake Inhibitors 40 ACE Inhibitors 111 HMG-CoA Inhibitors 134 PAF Antagonists 49 TXA2 Antagonists 574 "Inactives" Retrospective Validation • Briem& Lesselcompound library • 957 compound subset MDL Drug Data Report (MDDR) classified by biological activity  • Query result enriched in the biological activity of the query compound.

  6. Serotonin Re-uptake Inhibition SimFinder finds more active compounds

  7. Platelet Activating Factor Antagonist SimFinder finds more active compounds

  8. Thromboxane A2 Antagonist SimFinder finds more active compounds

  9. BACE-1 & BBB Permeability Studies • ChemBridge library filtered to remove reactive functional groups + Acelot Blood Brain Barrier permeability filters • AcelotSimFinder queries on curated library with known BACE-1 inhibitors • Compounds reviewed for medicinal chemistry considerations, ordered, and %-inhibition determined via in vitro BACE-1 assay.

  10. BACE-1 Study • Query Structures • Statines • Little overlap between GraphSim and Fingerprint similarity search results. •  Leads are • low MW • fragment-like • tractable with respect to Med. Chem. • Non-statins (hydroxyethyleneisostere) in hit list. • SimFinder search yields unique compounds and not "more-of-the-same".

  11. Summary of Retrospective Studies • Better than fingerprints via retrospective studies. • Complementary and unique query methods yield complementary and unique drug leads. • novel view of sample bank • new structural class of drug lead • topological approach yields unique structural classes of drug-leads for a given target class. • Chemical space explored is complementary to fingerprints or other non-toploogy based methods

  12. References • Huahai He; Ambuj K. Singh; Closure-tree: An Index Structure for Graph Queries. Proceedings of the 22nd International Conference on Data Engineering (ICDE), April, 2006, pp 38 - 50 DOI :10.1109/ICDE.2006.37. • Hans Briem and Uta F Lessel, Perspect. Drug Discov. Dec. 2000 (20), 231-244.

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