关键词: 抑制剂, 分子动力学, 线性响应理论, 自由能, 锌离子, 药物, 结合能, 分子设计

The absolute binding affinities of a series of hydroxamate inhibitors with MMP-2 were evaluated by molecular dynamics (MD) simulations with a linear response approach. During MD simulations, a nonboned model for the catalytic zinc center was used to represent the interactions between zinc center and enzyme/inhibitor. The trajectories from MD simulation show that using the nonbonded model the catalytic zinc ion adopts five coordination number, but the coordination form exists large difference with that of the initial model. After fittings, the models with one parameter, two parameters adn three parameters were obtained. The calculated results indicate that the three-parameter model with a constant term bears the best predicting ability. The best model yields an average error of 2.38 kJ/mol for the eight binding affinities of hydroxamtes.

Key words: INHIBITOR, MOLECULAR DYNAMICS, LINEAR RESPONSE THEORY, FREE ENERGY, ZINC ION, DRUGS, BINDING ENERGY, MOLECULAR DESIGN