title: Systematic exploitation of multiple receptor conformations for virtual ligand screening.
abstract: The role of virtual ligand screening in modern drug discovery is to mine large chemical collections and to prioritize for experimental testing a comparatively small and diverse set of compounds with expected activity against a target. Several studies have pointed out that the performance of virtual ligand screening can be improved by taking into account receptor flexibility. Here, we systematically assess how multiple crystallographic receptor conformations, a powerful way of discretely representing protein plasticity, can be exploited in screening protocols to separate binders from non-binders. Our analyses encompass 36 targets of pharmaceutical relevance and are based on actual molecules with reported activity against those targets. The results suggest that an ensemble receptor-based protocol displays a stronger discriminating power between active and inactive molecules as compared to its standard single rigid receptor counterpart. Moreover, such a protocol can be engineered not only to enrich a higher number of active compounds, but also to enhance their chemical diversity. Finally, some clear indications can be gathered on how to select a subset of receptor conformations that is most likely to provide the best performance in a real life scenario.
authors.affiliation: Department of Drug Discovery and Development, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.forename: Walter
authors.initials: W
authors.lastname: Rocchia
authors.forename: Manuel
authors.initials: M
authors.lastname: Rueda
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D000465:Algorithms; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D006801:Humans; D008024:Ligands; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D011956:Receptors, Cell Surface