Smith R H, Jorgensen W L, Tirado-Rives J, Lamb M L, Janssen P A, Michejda C J, Kroeger Smith M B
Department of Chemistry, Western Maryland College, Westminster, Maryland 21157, USA.
J Med Chem. 1998 Dec 17;41(26):5272-86. doi: 10.1021/jm9804174.
Monte Carlo (MC) simulations in combination with a linear response approach were used to estimate the free energies of binding for a series of 12 TIBO nonnucleoside inhibitors of HIV-1 reverse transcriptase. Separate correlations were made for the R6 and S6 absolute conformations of the inhibitors, as well as for the analogous N6-monoprotonated species. Models based upon the neutral unbound inhibitors produced overall better fits to experimental values than did those using the protonated unbound inhibitors, with only slight differences between the neutral R6 and S6 cases. The best results were obtained with a three-parameter linear response equation containing van der Waals (alpha), electrostatic (beta), and solvent accessible surface area (SASA, gamma) terms. The averaged (R6 and S6) rms error was approximately 0.88 kcal/mol for the observed range of 4.06 kcal/mol in inhibitor activities. The averaged values of alpha, beta, and gamma were -0.150, 0.114, and 0. 0286, respectively. Omission of the alpha term gave beta 0.152 and gamma 0.022 with a rms of 0.92. The unweighted van der Waals components were found to be highly attractive but failed to correlate well across the series of inhibitors. Contrastingly, while the electrostatic components are all repulsive, they show a direct correlation with inhibitor activity as measured by DeltaGbinding. The role of gamma is primarily to produce an overall negative binding energy, and it can effectively be replaced with a negative constant. During the MC simulations of the unbound solvated inhibitors, the R6 and S6 absolute conformations do not interconvert due to the formation of a favorable hydrogen bond to solvent. In the complex, however, interconversion of these conformations of the inhibitor is observed during the course of the simulations, a phenomenon which is apparently not observed in the crystalline state of the complex. Hydrogen bonding of the inhibitor to the backbone NH of K101 and the lack of such an interaction with the C=O of K101 or with solvent correlate with enhanced activity, as does the ability to assume a number of different orientations of the inhibitor dimethylallyl moiety with respect to residues Y181 and Y188 while retaining contact with W229. Overall, the use of a combination of MC simulation with a linear response method shows promise as a relatively rapid means of estimating inhibitor activities. This approach should be useful in the preliminary evaluation of potential modifications to known inhibitors to enhance activity.
结合线性响应方法的蒙特卡罗（MC）模拟被用于估算一系列12种HIV-1逆转录酶的替勃龙非核苷抑制剂的结合自由能。针对抑制剂的R6和S6绝对构象以及类似的N6-单质子化物种分别进行了相关性分析。基于中性未结合抑制剂构建的模型对实验值的总体拟合效果优于使用质子化未结合抑制剂构建的模型，中性R6和S6情况之间仅有细微差异。使用包含范德华力（α）、静电作用（β）和溶剂可及表面积（SASA，γ）项的三参数线性响应方程获得了最佳结果。在抑制剂活性4.06千卡/摩尔的观测范围内，平均（R6和S6）均方根误差约为0.88千卡/摩尔。α、β和γ的平均值分别为-0.150、0.114和0.0286。省略α项后，β为0.152，γ为0.022，均方根为0.92。发现未加权的范德华力成分具有很强的吸引力，但在一系列抑制剂中相关性不佳。相反，虽然静电成分都是排斥性的，但它们与通过结合自由能（ΔGbinding）测量的抑制剂活性呈直接相关性。γ的作用主要是产生总体负结合能，并且它可以有效地用一个负常数代替。在未结合的溶剂化抑制剂的MC模拟过程中，由于与溶剂形成了有利的氢键，R6和S6绝对构象不会相互转化。然而，在复合物中，在模拟过程中观察到抑制剂这些构象的相互转化，这种现象在复合物的晶体状态中显然未被观察到。抑制剂与K101主链NH的氢键作用以及与K101的C=O或与溶剂缺乏这种相互作用与活性增强相关，抑制剂二甲基烯丙基部分相对于残基Y181和Y188能够呈现多种不同取向同时保持与W229接触的能力也与活性增强相关。总体而言，将MC模拟与线性响应方法结合使用显示出作为一种相对快速估算抑制剂活性的方法的前景。这种方法在对已知抑制剂进行潜在修饰以增强活性的初步评估中应该是有用的。
