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

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Mariela Bollini†, Robert A. Domaoal‡, Vinay V. Thakur†, Ricardo Gallardo-Macias†, Krasimir A. Spasov‡, Karen S. Anderson*‡, and William L. Jorgensen*†

Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520-8066, United States

J. Med. Chem., 2011, 54 (24), pp 8582–8591

DOI: 10.1021/jm201134m

Publication Date (Web): November 14, 2011

(K.S.A.) Phone: 203-785-4526. Fax: 203-785-7670. E-mail: karen.anderson@yale.edu. (W.L.J.) Phone: 203-432-6278. Fax: 203-432-6299. E-mail: william.jorgensen@yale.edu.

Section:

Benzene, Its Derivatives, and Condensed Benzenoid Compounds

Abstract

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.

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History

Published In Issue December 22, 2011
Article ASAPNovember 29, 2011
Just Accepted ManuscriptNovember 14, 2011
Received: August 24, 2011

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

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Related Content

Benzimidazolones: A New Class of Selective Peroxisome Proliferator-Activated Receptor γ (PPARγ) Modulators

Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists

Structure-Guided Evolution of Potent and Selective CHK1 Inhibitors through Scaffold Morphing

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