Guillaume Bouvier1, Nathalie Evrard-Todeschi, Jean-Pierre Girault, Gildas Bertho. 1. Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, Unité Mixte de Recherche 8601, Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes, 45 rue des Saints-Pères, 75006 Paris, France.
Abstract
MOTIVATION: Scoring functions provided by the docking software are still a major limiting factor in virtual screening (VS) process to classify compounds. Score analysis of the docking is not able to find out all active compounds. This is due to a bad estimation of the ligand binding energies. Making the assumption that active compounds should have specific contacts with their target to display activity, it would be possible to discriminate active compounds from inactive ones with careful analysis of interatomic contacts between the molecule and the target. However, compounds clustering is very tedious due to the large number of contacts extracted from the different conformations proposed by docking experiments. RESULTS: Structural analysis of docked structures is processed in three steps: (i) a Kohonen self-organizing map (SOM) training phase using drug-protein contact descriptors followed by (ii) an unsupervised cluster analysis and (iii) a Newick file generation for results visualization as a tree. The docking poses are then analysed and classified quickly and automatically by AuPosSOM (Automatic analysis of Poses using SOM). AuPosSOM can be integrated into strategies for VS currently employed. We demonstrate that it is possible to discriminate active compounds from inactive ones using only mean protein contacts' footprints calculation from the multiple conformations given by the docking software. Chemical structure of the compound and key binding residues information are not necessary to find out active molecules. Thus, contact-activity relationship can be employed as a new VS process. AVAILABILITY: AuPosSOM is available at http://www.aupossom.com.
MOTIVATION: Scoring functions provided by the docking software are still a major limiting factor in virtual screening (VS) process to classify compounds. Score analysis of the docking is not able to find out all active compounds. This is due to a bad estimation of the ligand binding energies. Making the assumption that active compounds should have specific contacts with their target to display activity, it would be possible to discriminate active compounds from inactive ones with careful analysis of interatomic contacts between the molecule and the target. However, compounds clustering is very tedious due to the large number of contacts extracted from the different conformations proposed by docking experiments. RESULTS: Structural analysis of docked structures is processed in three steps: (i) a Kohonen self-organizing map (SOM) training phase using drug-protein contact descriptors followed by (ii) an unsupervised cluster analysis and (iii) a Newick file generation for results visualization as a tree. The docking poses are then analysed and classified quickly and automatically by AuPosSOM (Automatic analysis of Poses using SOM). AuPosSOM can be integrated into strategies for VS currently employed. We demonstrate that it is possible to discriminate active compounds from inactive ones using only mean protein contacts' footprints calculation from the multiple conformations given by the docking software. Chemical structure of the compound and key binding residues information are not necessary to find out active molecules. Thus, contact-activity relationship can be employed as a new VS process. AVAILABILITY: AuPosSOM is available at http://www.aupossom.com.