Analyses of activity for factor Xa inhibitors based on Monte Carlo simulations.
Analyses of activity for factor Xa inhibitors based on Monte Carlo simulations.
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基于蒙特卡罗模拟的 Xa 因子抑制剂活性分析。
DOI：
10.1021/jm030288d
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发表时间：
2003
期刊：
影响因子：
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通讯作者：
Jorgensen,WilliamL
中科院分区：
文献类型：
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作者：
Ostrovsky,Dennis;Udier-Blagovic,Marina;Jorgensen,WilliamL
对 60 种人类 Xa 因子抑制剂进行了蒙特卡罗/扩展线性响应 (MC/ELR) 模拟，以确定与其活性相关的重要相互作用。在模拟与因子 Xa 结合和游离于水中的每种抑制剂的过程中，对各种物理化学描述符进行构型平均。然后得出回归方程；它仅使用两个物理上合理的描述符即可重现实验抑制数据，相关系数 r2 为 0.74，均方根误差为 0.67 kcal/mol，平均无符号误差为 0.60 kcal/mol。在确定抑制潜力时出现的两个重要因素是（1）蛋白质和配体之间有利的范德华相互作用，以及（2）抑制剂和蛋白质之间的直接氢键。这些结论得到了结构分析和 MC/自由能微扰 (FEP) 计算结果的支持。
Monte Carlo/Extended Linear Response (MC/ELR) simulations have been conducted on 60 inhibitors of human factor Xa to determine the important interactions associated with their activity. A variety of physicochemical descriptors were configurationally averaged during the course of the simulations of each inhibitor bound to factor Xa and free in water. A regression equation was then derived; it reproduces the experimental inhibition data with a correlation coefficient,r2, of 0.74, an rms error of 0.67 kcal/mol, and an average unsigned error of 0.60 kcal/mol using only two physically reasonable descriptors. The two factors that emerged as important in determining inhibitory potential are (1) favorable van der Waals interactions between protein and ligand and (2) direct hydrogen bonding between the inhibitor and protein. The conclusions were supported with structural analyses and results of MC/free energy perturbation (FEP) calculations.