Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States.
J Med Chem. 2011 Dec 22;54(24):8582-91. doi: 10.1021/jm201134m. Epub 2011 Nov 29.
A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (FEP) calculations to predict relative free energies of binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most potent resultant catechol diethers feature terminal uracil and cyanovinylphenyl groups. A halogen bond with Pro95 likely contributes to the extreme potency of compound 42. In addition, several examples are provided illustrating failures of attempted grafting of a substructure from a very active compound onto a seemingly related scaffold to improve its activity.
已将 5 μM 的对接命中物优化为一种极其有效的(55 pM)非核苷 HIV 逆转录酶抑制剂。使用自由能微扰(FEP)计算来预测相对结合自由能有助于通过确定苯环和连接子的最佳取代模式来进行优化。最有效的结果儿茶酚二醚具有末端尿嘧啶和氰乙烯基苯基基团。与 Pro95 的卤键可能有助于化合物 42 的极高效力。此外,还提供了几个示例,说明了试图将一个非常活跃的化合物的亚结构嫁接到一个看似相关的支架上以提高其活性的尝试失败。