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

被引：108

作者：

Bollini, Mariela ^{[2
]}

Domaoal, Robert A. ^{[1
]}

Thakur, Vinay V. ^{[2
]}

Gallardo-Macias, Ricardo ^{[2
]}

Spasov, Krasimir A. ^{[1
]}

Anderson, Karen S. ^{[1
]}

Jorgensen, William L. ^{[2
]}

机构：

[1] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA

[2] Yale Univ, Dept Chem, New Haven, CT 06520 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 24期

基金：

美国国家卫生研究院;

关键词：

REVERSE-TRANSCRIPTASE INHIBITORS; NONNUCLEOSIDE INHIBITORS; BIOMOLECULAR SYSTEMS; ANTIVIRAL ACTIVITY; CRYSTAL-STRUCTURE; DISCOVERY; DRUG; DESIGN; DERIVATIVES; MUTATIONS;

D O I：

10.1021/jm201134m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A 5-mu M docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use of free energy perturbation (PEP) 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.

引用

页码：8582 / 8591

页数：10

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