Skip to main content

Advertisement

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 [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.

References

  1. 1.

    Weininger D, et al: J Chem Inf Comput Sci. 1989, 29: 97-

  2. 2.

    Needleman S, Wunsch C: J Mol Biol. 1970, 48: 443-10.1016/0022-2836(70)90057-4.

  3. 3.

    Schneider G, et al: Angew Chem Int Ed. 1999, 38: 2894-10.1002/(SICI)1521-3773(19991004)38:19<2894::AID-ANIE2894>3.0.CO;2-F.

  4. 4.

    Sheridan RP, et al: J Chem Inf Comput Sci. 1996, 36: 128-

  5. 5.

    Schneider P, Schneider G: QSAR Comb Sci. 2003, 22: 713-10.1002/qsar.200330825.

Download references

Author information

Correspondence to V Hähnke.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 2.0 International License (https://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Reprints and Permissions

About this article

Keywords

  • Virtual Screening
  • Lead Structure
  • Identical Topology
  • Compound Database
  • Pairwise Sequence Alignment