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

ABSTRACT: A 5-?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.

SUBMITTER: Bollini M

PROVIDER: S-EPMC3258498 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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

Bollini Mariela M Domaoal Robert A RA Thakur Vinay V VV Gallardo-Macias Ricardo R Spasov Krasimir A KA Anderson Karen S KS Jorgensen William L WL

Journal of medicinal chemistry 20111129 24

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 compou ...[more]

PMID: 22081993

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