Computationally-Guided Optimization of a Docking Hit to Yield Catechol Diethers as Potent Anti-HIV Agents

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• 作者：Mariela Bollini ; Robert A. Domaoal ; Vinay V. Thakur ; Ricardo Gallardo-Macias ; Krasimir A. Spasov ; Karen S. Anderson ; William L. Jorgensen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8582-8591
• 全文大小：569K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

A 5-渭M 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.