人类免疫缺陷病毒1型逆转录酶非核苷抑制剂的计算机辅助设计
Computer-aided design of non-nucleoside inhibitors of HIV-1 reverse transcriptase.
作者信息
Jorgensen William L, Ruiz-Caro Juliana, Tirado-Rives Julian, Basavapathruni Aravind, Anderson Karen S, Hamilton Andrew D
机构信息
Department of Chemistry, Yale University, New Haven, CT 06520-8107, USA.
出版信息
Bioorg Med Chem Lett. 2006 Feb;16(3):663-7. doi: 10.1016/j.bmcl.2005.10.038. Epub 2005 Nov 2.
Design principles are delineated for non-nucleoside inhibitors for HIV-1 reverse transcriptase (NNRTIs). Simultaneous optimization of binding affinity for wild-type RT, tolerance for viral mutations, and physical properties is pursued. Automated lead generation with the growing program BOMB, Monte Carlo simulations with free-energy perturbation theory for lead optimization, and property analysis with QikProp are featured. An initial 30 microM lead has been optimized rapidly to the 10 nM level.
阐述了针对HIV-1逆转录酶（非核苷类逆转录酶抑制剂，NNRTIs）的非核苷抑制剂的设计原则。致力于同时优化对野生型逆转录酶的结合亲和力、对病毒突变的耐受性以及物理性质。重点介绍了使用不断发展的程序BOMB进行自动先导化合物生成、使用自由能微扰理论进行蒙特卡罗模拟以优化先导化合物，以及使用QikProp进行性质分析。一种初始浓度为30微摩尔的先导化合物已迅速优化至10纳摩尔水平。
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