Estimation of binding affinities for HEPT and nevirapine analogues with HIV-1 reverse transcriptase via Monte Carlo simulations.
Estimation of binding affinities for HEPT and nevirapine analogues with HIV-1 reverse transcriptase via Monte Carlo simulations.
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通过蒙特卡罗模拟估计 HEPT 和奈韦拉平类似物与 HIV-1 逆转录酶的结合亲和力。
DOI：
10.1021/jm000255n
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发表时间：
2001
影响因子：
7.3
通讯作者：
Jorgensen,WL
中科院分区：
文献类型：
--
作者：
Rizzo,RC;Tirado-Rives,J;Jorgensen,WL
与 20 种 HEPT 和 20 种奈韦拉平 HIV-1 逆转录酶 (RT) 非核苷抑制剂结合相关的相互作用和能量学已得到探索，旨在建立可用于开发更有效的抗 HIV 药物的模拟方案和方法。以晶体结构为起点，通过蒙特卡罗 (MC) 统计力学方法对所有 40 种抑制剂的结合和非结合状态进行建模。在 MC 模拟过程中，对每种抑制剂的潜在有用的结合亲和力描述符进行了构型平均，并寻求与报告的实验活动的相关性。仅使用四个描述符将 40 个实验活动与 0.75 的 anr2 和 0.69 的交叉验证q2 相关联，就获得了可行的回归方程。与实验相比，计算出的活性显示 rmsd 为 0.94 kcal/mol，平均无符号误差为 0.69 kcal/mol。 MC结果揭示了控制结合亲和力的三个物理上合理的参数： （1）与抑制剂的氢键损失是不利的，（2）疏水表面区域的埋藏是有利的，以及（3）蛋白质-抑制剂复合物需要良好的几何拟合而没有空间冲突。令人欣慰的是，相应的描述符在统计上是确定 40 种化合物的抗 HIVRT 活性的最重要的量。还给出了代表性示例，其中使用 MC 模拟的结构和热力学信息来帮助了解相关化合物的结合差异。在二级酰胺奈韦拉平类似物和 HIVRT 的 Tyr188A 之间发现了一个关键的 π 型氢键，这解释了它们原本令人惊讶的活性以及奈韦拉平对 Y188C 突变体的无效性。
The interactions and energetics associated with the binding of 20 HEPT and 20 nevirapine nonnucleoside inhibitors of HIV-1 reverse transcriptase (RT) have been explored in an effort to establish simulation protocols and methods that can be used in the development of more effective anti-HIV drugs. Using crystallographic structures as starting points, all 40 inhibitors were modeled in the bound and unbound states via Monte Carlo (MC) statistical mechanics methods. Potentially useful descriptors of binding affinity were configurationally averaged for each inhibitor during the MC simulations, and correlations were sought with reported experimental activities. A viable regression equation was obtained using only four descriptors to correlate the 40 experimental activities with anr2of 0.75 and cross-validatedq2of 0.69. The computed activities show a rmsd of 0.94 kcal/mol in comparison with experiment and an average unsigned error of 0.69 kcal/mol. The MC results reveal three physically reasonable parameters that control the binding affinities: (1) loss of hydrogen bonds with the inhibitor is unfavorable, (2) burial of hydrophobic surface area is favorable, and (3) a good geometrical fit without steric clashes is needed for the protein−inhibitor complex. It is gratifying that the corresponding descriptors are statistically the most important quantities for determining the anti-HIVRT activity for the 40 compounds. Representative examples are also given in which structural and thermodynamic information from the MC simulations is used to help understand binding differences for related compounds. A key π-type hydrogen bond has been identified between secondary-amide nevirapine analogues and Tyr188A of HIVRT that explains their otherwise surprising activity and the ineffectiveness of nevirapine against the Y188C mutant.