title: A Collective Variable for the Rapid Exploration of Protein Druggability.
abstract: An efficient molecular simulation methodology has been developed for the evaluation of the druggability (ligandability) of a protein. Previously proposed techniques were designed to assess the druggability of crystallographic structures and cannot be tightly coupled to molecular dynamics (MD) simulations. By contrast, the present approach, JEDI (Just Exploring Druggability at protein Interfaces), features a druggability potential made of a combination of empirical descriptors that can be collected "on-the-fly" during MD simulations. Extensive validation studies indicate that JEDI analyses discriminate druggable and nondruggable protein binding site conformations with accuracy similar to alternative methodologies, and at a fraction of the computational cost. Since the JEDI function is continuous and differentiable, the druggability potential can be used as collective variable to rapidly detect cryptic druggable binding sites in proteins with a variety of MD free energy methods. Protocols for applications to flexible docking problems are outlined.
authors.affiliation: EaStCHEM School of Chemistry , Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
authors.forename: Rémi
authors.initials: R
authors.lastname: Cuchillo
authors.affiliation: EaStCHEM School of Chemistry , Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
authors.forename: Kevin
authors.initials: K
authors.lastname: Pinto-Gil
authors.affiliation: EaStCHEM School of Chemistry , Joseph Black Building, West Mains Road, Edinburgh EH9 3JJ, United Kingdom.
authors.forename: Julien
authors.initials: J
authors.lastname: Michel
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins