Free-energy-based methods for binding profile determination in a congeneric series of CDK2 inhibitors.
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.
Fidelak
Jérémy
J
Chemical and Analytical Sciences/In Silico Sciences, Sanofi-Aventis SA, 195 route d'Espagne, Toulouse, France.
Juraszek
Jarek
J
Branduardi
Davide
D
Bianciotto
Marc
M
Gervasio
Francesco Luigi
FL
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
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2