title: Free-energy-based methods for binding profile determination in a congeneric series of CDK2 inhibitors.
abstract: Free-energy pathway methods show great promise in computing the mode of action and the free energy profile associated with the binding of small molecules with proteins, but are generally very computationally demanding. Here we apply a novel approach based on metadynamics and path collective variables. We show that this combination is able to find an optimal reaction coordinate and the free energy profile of binding with explicit solvent and full flexibility, while minimizing human intervention and computational costs. We apply it to predict the binding affinity of a congeneric series of 5 CDK2 inhibitors. The predicted binding free energy profiles are in accordance with experiment.
authors.affiliation: Chemical and Analytical Sciences/In Silico Sciences, Sanofi-Aventis SA, 195 route d'Espagne, Toulouse, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Fidelak
authors.forename: Jarek
authors.initials: J
authors.lastname: Juraszek
authors.forename: Davide
authors.initials: D
authors.lastname: Branduardi
authors.forename: Marc
authors.initials: M
authors.lastname: Bianciotto
authors.forename: Francesco Luigi
authors.initials: FL
authors.lastname: Gervasio
mesh_terms: D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2