Drug binding kinetics and drug residence time is identified as an essential parameter for drug discovery. Here we present a computational technique, and a computational package to estimate the protein-ligand binding kinetics describing the factors assisting the drug-design. The method uses molecular dynamics simulations and partitions the dissociation pathway in the number of milestones. The computational package uses a novel strategy to define the milestones by analyzing dissociation pathways obtained by a sampling method. We applied the package to estimate the free energy barriers and residence time of a model system consisting of P38 MAP kinase and SB2 (SmithKline Beecham) ligand. The calculated binding free energy well agree with the measured values, and critical intermediate barriers along the dissociation path of the system as mentioned earlier were identified using the package.

Milestone based computational approach to estimate energy barriers in the drug designing, and application to P38-MAP kinase-SB2 system

2019 Fall National Meeting

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