Rapid Estimation of Relative Protein-Ligand Binding Affinities Using a High-Throughput Version of MM-PBSA

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• 作者：Scott P. Brown ; Steven W. Muchmore
• 刊名：Journal of Chemical Information and Modeling
• 出版年：2007
• 出版时间：July 2007
• 年：2007
• 卷：47
• 期：4
• 页码：1493 - 1503
• 全文大小：481K
• 年卷期：v.47,no.4(July 2007)
• ISSN：1549-960X

文摘

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 relativeestimates of protein-ligand binding affinities. The modified method uses a generalized Born implicit solvationmodel 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 constructionallows for reduction of the computational cost of the calculations by roughly 2 orders of magnitude comparedto the traditional formulation of MM-PBSA. With this high-throughput version of MM-PBSA we show thatone can produce efficient physics-based estimates of relative binding free energies with reasonable correlationto experimental data and a total computation time that is sufficiently low such that an industrially relevantthroughput can be realized given currently accessible computing resources. We demonstrate this approachby performing a comparison of different MM-PBSA implementations on a set of 18 ligands for the proteintarget urokinase.