Rapid estimation of relative protein-ligand binding affinities using a high-throughput version of MM-PBSA |
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Authors: | Brown Scott P Muchmore Steven W |
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Affiliation: | Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA. scott.brown@abbott.com |
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Abstract: | By employing a modified protocol of the Molecular Mechanics with Poisson-Boltzmann Surface Area (MM-PBSA) methodology we substantially decrease the required computation time for calculating relative estimates of protein-ligand binding affinities. The modified method uses a generalized Born implicit solvation model during molecular dynamics to enhance conformational sampling as well as a very efficient Poisson-Boltzmann solver and a computational design based on a distributed-computing paradigm. This construction allows for reduction of the computational cost of the calculations by roughly 2 orders of magnitude compared to the traditional formulation of MM-PBSA. With this high-throughput version of MM-PBSA we show that one can produce efficient physics-based estimates of relative binding free energies with reasonable correlation to experimental data and a total computation time that is sufficiently low such that an industrially relevant throughput can be realized given currently accessible computing resources. We demonstrate this approach by performing a comparison of different MM-PBSA implementations on a set of 18 ligands for the protein target urokinase. |
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