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Greedy 3-Point Search (G3PS)—A Novel Algorithm for Pharmacophore Alignment
Authors:Christian Permann  Thomas Seidel  Thierry Langer
Affiliation:1.Department of Pharmaceutical Sciences, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria; (C.P.); (T.L.);2.Inte:Ligand GmbH, Clemens Maria Hofbauer-Gasse 6, 2344 Maria Enzersdorf, Austria
Abstract:Chemical features of small molecules can be abstracted to 3D pharmacophore models, which are easy to generate, interpret, and adapt by medicinal chemists. Three-dimensional pharmacophores can be used to efficiently match and align molecules according to their chemical feature pattern, which facilitates the virtual screening of even large compound databases. Existing alignment methods, used in computational drug discovery and bio-activity prediction, are often not suitable for finding matches between pharmacophores accurately as they purely aim to minimize RMSD or maximize volume overlap, when the actual goal is to match as many features as possible within the positional tolerances of the pharmacophore features. As a consequence, the obtained alignment results are often suboptimal in terms of the number of geometrically matched feature pairs, which increases the false-negative rate, thus negatively affecting the outcome of virtual screening experiments. We addressed this issue by introducing a new alignment algorithm, Greedy 3-Point Search (G3PS), which aims at finding optimal alignments by using a matching-feature-pair maximizing search strategy while at the same time being faster than competing methods.
Keywords:pharmacophore alignment   pharmacophore modelling   virtual screening   greedy algorithm   drug design
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