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Molecules 2015, 20(5), 8997-9028;

S4MPLE—Sampler for Multiple Protein-Ligand Entities: Methodology and Rigid-Site Docking Benchmarking

Laboratoire de Chemoinformatique; UMR 7141, Université de Strasbourg, 1 rue B. Pascal, Strasbourg 67000, France
Novalix, BioParc, bld Sébastien Brant, BP 30170, Illkirch 67405 Cedex, France
Department of Computer Science, Technical University, Cluj-Napoca 400027, Romania
Author to whom correspondence should be addressed.
Academic Editor: Rino Ragno
Received: 5 March 2015 / Revised: 27 April 2015 / Accepted: 11 May 2015 / Published: 19 May 2015
(This article belongs to the Special Issue Molecular Docking in Drug Design)
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This paper describes the development of the unified conformational sampling and docking tool called Sampler for Multiple Protein-Ligand Entities (S4MPLE). The main novelty in S4MPLE is the unified dealing with intra- and intermolecular degrees of freedom (DoF). While classically programs are either designed for folding or docking, S4MPLE transcends this artificial specialization. It supports folding, docking of a flexible ligand into a flexible site and simultaneous docking of several ligands. The trick behind it is the formal assimilation of inter-molecular to intra-molecular DoF associated to putative inter-molecular contact axes. This is implemented within the genetic operators powering a Lamarckian Genetic Algorithm (GA). Further novelty includes differentiable interaction fingerprints to control population diversity, and fitting a simple continuum solvent model and favorable contact bonus terms to the AMBER/GAFF force field. Novel applications—docking of fragment-like compounds, simultaneous docking of multiple ligands, including free crystallographic waters—were published elsewhere. This paper discusses: (a) methodology, (b) set-up of the force field energy functions and (c) their validation in classical redocking tests. More than 80% success in redocking was achieved (RMSD of top-ranked pose < 2.0 Å). View Full-Text
Keywords: genetic algorithms; conformational sampling; docking; interaction fingerprints; force field fitting genetic algorithms; conformational sampling; docking; interaction fingerprints; force field fitting

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Hoffer, L.; Chira, C.; Marcou, G.; Varnek, A.; Horvath, D. S4MPLE—Sampler for Multiple Protein-Ligand Entities: Methodology and Rigid-Site Docking Benchmarking. Molecules 2015, 20, 8997-9028.

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