Computationally-guided optimization of a docking hit to yield catechol diethers as potent anti-HIV agents

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

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

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. (Figure presented)

Original languageEnglish (US)
Pages (from-to)8582-8591
Number of pages10
JournalJournal of medicinal chemistry
Volume54
Issue number24
DOIs
StatePublished - Dec 22 2011

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