Chemistry Central Journal

© Hähnke et al; licensee BioMed Central Ltd. 2009

This article is published under license to BioMed Central Ltd.

10.1186/1752-153X-3-S1-P67

Poster presentation

PhAST: pharmacophore alignment search tool

V Hähnke1 , B Hofmann¹, E Proschak¹, D Steinhilber¹ and G Schneider¹

(1)

Johann Wolfgang Goethe-University, Beilstein Endowed Chair for Chem-and Bioinformatics, Institut für Organische Chemie und Chemische Biologie, Siesmayerstr 70, D-60323 Frankfurt am Main, Germany

Published online: 05 June 2009

We developed the Pharmacophore Alignment Search Tool (PhAST), a text-based technique for rapid hit and lead structure searching in large compound databases. For each molecule, a two-dimensional graph of potential pharmacophoric points (PPPs) is created, which has an identical topology as the original molecule with implicit hydrogen atoms. Each vertex is coloured by a symbol representing the corresponding PPP. The vertices of the graph are canonically labelled [1]. The symbols associated with the vertices are combined to a so-called PhAST-Sequence beginning with the vertex with the lowest canonical label. Due to the canonical labelling the created PhAST-Sequence is characteristic for each molecule.

For similarity assessment, PhAST-Sequences are compared using the sequence identity in their global pairwise alignment [2]. The alignment score lies between 0 (no similarity) and 1 (identical PhAST-Sequences). In order to use global pairwise sequence alignment, a score matrix for pharmacophoric symbols was developed and gap penalties were optimized. PhAST performed comparably and sometimes superior to other similarity search tools (CATS2D [3], MOE pharmacophore quadruples [4]) in retrospective virtual screenings using the COBRA [5] collection of drugs and lead structures. Most importantly, the PhAST alignment technique allows for the computation of significance estimates that help prioritize a virtual hit list.

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