PhAST : pharmacophore alignment search tool

  • 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. 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. 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, MOE pharmacophore quadruples) in retrospective virtual screenings using the COBRA 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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Author:Volker Dirk Hähnke, Bettina Petra Hofmann, Ewgenij ProschakORCiDGND, Dieter SteinhilberORCiDGND, Gisbert SchneiderORCiDGND
Parent Title (English):Chemistry central journal
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Year of Completion:2009
Date of first Publication:2009/06/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Contributing Corporation:4th German Conference on Chemoinformatics: 22. CIC-Workshop
Release Date:2009/08/26
Tag:Compound Database; Identical Topology; Lead Structure; Pairwise Sequence Alignment; Virtual Screening
Issue:(Suppl 1):P67
Page Number:1
First Page:1
Last Page:1
© 2009 Hähnke et al; licensee BioMed Central Ltd.
Source:4th German Conference on Chemoinformatics Goslar, Germany. 9–11 November 2008 ; Chemistry Central Journal 2009, 3(Suppl 1):P67 ; doi:10.1186/1752-153X-3-S1-P67 ;
Institutes:Biochemie, Chemie und Pharmazie / Biochemie und Chemie
Biochemie, Chemie und Pharmazie / Pharmazie
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 54 Chemie / 540 Chemie und zugeordnete Wissenschaften
Licence (German):License LogoDeutsches Urheberrecht