Multisite λ Dynamics for Simulated Structure-Activity Relationship Studies
Multisite λ Dynamics for Simulated Structure-Activity Relationship Studies
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DOI：
10.1021/ct200444f
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发表时间：
2011-09-01
影响因子：
5.5
通讯作者：
Brooks, Charles L., III
中科院分区：
文献类型：
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作者：
Knight, Jennifer L.;Brooks, Charles L., III
多站lambda动力学（MS lambda D）是一种基于lambda动力学的新的自由能模拟方法。它已被开发，使多个取代基在多个网站上的一个共同的配体核心被建模，同时评估其自由能。MS λ D估计相对水合自由能和相对结合亲和力的功效证明使用三个测试系统。代表多个相同的苯，二羟基苯，和二甲氧基苯分子表明，类似于1.5 ns的总组合MS λ D轨迹长度足以可靠地实现0.2 kcal/s内的相对水合自由能估计值。摩尔和不太敏感的轨迹的数量，用于产生这些估计的混合配体，含有多达10个取代基建模在一个单一的在两个位点中的每一个上模拟五个取代基。由MS λ D模拟计算的六种苯衍生物的相对水合自由能与炼金术自由能模拟（平均无符号误差为0.23 kcal/mol，R-2 = 0.991）和实验（平均无符号误差为1.8 kcal/mol，R-2 = 0.959）的结果非常一致。从MS λ D模拟获得的14种HIV-1逆转录酶抑制剂之间的相对结合亲和力的估计值与传统自由能模拟和实验结果（平均无符号误差为0.9 kcal/mol，R-2 = 0.402）合理一致。对于相同水平的准确度和精度，MS lambda D模拟比传统的自由能模拟快20-50倍，因此具有可靠的力场参数，可以有效地用于筛选基于结构的药物设计应用中的数十至数百种化合物。
Multisite lambda dynamics (MS lambda D) is a new free energy simulation method that is based on lambda dynamics. It has been developed to enable multiple substituents at multiple sites on a common ligand core to be modeled simultaneously and their free energies assessed. The efficacy of MS lambda D for estimating relative hydration free energies and relative binding affinties is demonstrated using three test systems. Model compounds representing multiple identical benzene, dihydroxybenzene, and dimethoxybenzene molecules show that total combined MS lambda D trajectory lengths of similar to 1.5 ns are sufficient to reliably achieve relative hydration free energy estimates within 0.2 kcal/mol and are less sensitive to the number of trajectories that are used to generate these estimates for hybrid ligands that contain up to 10 substituents modeled at a single site or five substituents modeled at each of two sites. Relative hydration free energies among six benzene derivatives calculated from MS lambda D simulations are in very good agreement with those from alchemical free energy simulations (with average unsigned differences of 0.23 kcal/mol and R-2 = 0.991) and the experiment (with average unsigned errors of 1.8 kcal/mol and R-2 = 0.959). Estimates of the relative binding affinities among 14 inhibitors of HIV-1 reverse transcriptase obtained from MS lambda D simulations are in reasonable agreement with those from traditional free energy simulations and the experiment (average unsigned errors of 0.9 kcal/mol and R-2 = 0.402). For the same level of accuracy and precision, MS lambda D simulations are achieved similar to 20-50 times faster than traditional free energy simulations and thus with reliable force field parameters can be used effectively to screen tens to hundreds of compounds in structure-based drug design applications.