title: Pharmacophore alignment search tool: influence of scoring systems on text-based similarity searching.
abstract: The text-based similarity searching method Pharmacophore Alignment Search Tool is grounded on pairwise comparisons of potential pharmacophoric points between a query and screening compounds. The underlying scoring matrix is of critical importance for successful virtual screening and hit retrieval from large compound libraries. Here, we compare three conceptually different computational methods for systematic deduction of scoring matrices: assignment-based, alignment-based, and stochastic optimization. All three methods resulted in optimized pharmacophore scoring matrices with significantly superior retrospective performance in comparison with simplistic scoring schemes. Computer-generated similarity matrices of pharmacophoric features turned out to agree well with a manually constructed matrix. We introduce the concept of position-specific scoring to text-based similarity searching so that knowledge about specific ligand-receptor binding patterns can be included and demonstrate its benefit for hit retrieval. The approach was also used for automated pharmacophore elucidation in agonists of peroxisome proliferator activated receptor gamma, successfully identifying key interactions for receptor activation.
authors.affiliation: Swiss Federal Institute of Technology (ETH) Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Wolfgang-Pauli-Str. 10, 8093 Zürich, Switzerland.
authors.forename: Volker
authors.initials: V
authors.lastname: Hähnke
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000595:Amino Acid Sequence; D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D016247:Information Storage and Retrieval / Q000379:methods*; D047495:PPAR gamma / Q000819:agonists; D011485:Protein Binding; D057386:Search Engine / Q000379:methods; D016415:Sequence Alignment
chemical_list: D047495:PPAR gamma