Free-Energy-Based Methods for Binding Profile Determination in a Congeneric Series of CDK2 Inhibitors

• DOI: 10.1021/jp911689r
• Publication Date: 2010-07-02T11:13:47Z
• Authors: Jérémy Fidelak; Jarek Juraszek; Davide Branduardi; Marc Bianciotto; Francesco Luigi G...
• Keywords: 0303 health sciences; 03 medical and health sciences; Pyrimidines; Cyclin-Dependent Kinase 2; Humans; Thermodynamics; Molecular Dynamics Simulation; Protein Kinase Inhibitors; Protein Binding

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.