title: Molecular Dynamics Simulations and Kinetic Measurements to Estimate and Predict Protein-Ligand Residence Times.
abstract: Ligand-target residence time is emerging as a key drug discovery parameter because it can reliably predict drug efficacy in vivo. Experimental approaches to binding and unbinding kinetics are nowadays available, but we still lack reliable computational tools for predicting kinetics and residence time. Most attempts have been based on brute-force molecular dynamics (MD) simulations, which are CPU-demanding and not yet particularly accurate. We recently reported a new scaled-MD-based protocol, which showed potential for residence time prediction in drug discovery. Here, we further challenged our procedure's predictive ability by applying our methodology to a series of glucokinase activators that could be useful for treating type 2 diabetes mellitus. We combined scaled MD with experimental kinetics measurements and X-ray crystallography, promptly checking the protocol's reliability by directly comparing computational predictions and experimental measures. The good agreement highlights the potential of our scaled-MD-based approach as an innovative method for computationally estimating and predicting drug residence times.
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Mollica
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Theret
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Mathias
authors.initials: M
authors.lastname: Antoine
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Perron-Sierra
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Yves
authors.initials: Y
authors.lastname: Charton
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Fourquez
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Wierzbicki
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Ferry
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.|BiKi Technologies S.r.l. via XX Settembre 33/10 16121 Genova, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Decherchi
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.|BiKi Technologies S.r.l. via XX Settembre 33/10 16121 Genova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bottegoni
authors.affiliation: Institut de Recherches Servier , 125 Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Ducrot
authors.affiliation: CompuNet, Istituto Italiano di Tecnologia , via Morego 30, 16163 Genova, Italy.|Department of Pharmacy and Biotechnology, University of Bologna , via Belmeloro 6, 40126 Bologna, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Cavalli
mesh_terms: D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D008024:Ligands; D005941:Glucokinase