Greedy 3-Point Search (G3PS)-A Novel Algorithm for Pharmacophore Alignment.

Christian Permann,Thierry Langer,Thomas Seidel

doi:10.3390/molecules26237201

Christian Permann, Thierry Langer + Show 1 more

Open Access

https://doi.org/10.3390/molecules26237201

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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.

Highlights

The latter approach generally leads to higher quality models due to the availability of boundstate ligand structures and binding-site environment information
One of the most prominent application of pharmacophores is their use as a filter for the virtual screening of large compound libraries, which aims at finding molecules providing the same chemical feature pattern as specified by the query pharmacophore [5,8]
In the presented work, we address all of the above discussed main problems of the existing pharmacophore alignment methods 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

Summary

Introduction

The latter approach generally leads to higher quality models due to the availability of boundstate ligand structures and binding-site environment information. The obtained pharmacophores usually need to be further refined by an expert user towards higher quality regarding their ability to discriminate between active and inactive molecules [2]. Pharmacophore-based techniques have an inherent scaffold hopping ability, which is of high value for lead optimization tasks or the tailored design of drug molecule [7]. One of the most prominent application of pharmacophores is their use as a filter for the virtual screening of large compound libraries (for which pharmacophores have been pre-generated), which aims at finding molecules providing the same chemical feature pattern as specified by the query pharmacophore [5,8]. Found molecules where all or most of the query features match are likely to be active towards the target of interest and represent a good first set of candidates for further experimental activity analyses

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