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

doi:10.1021/jm201134m

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

Institute for Therapeutics Discovery and Development

Research output: Contribution to journal › Article › peer-review

112 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 language	English (US)
Pages (from-to)	8582-8591
Number of pages	10
Journal	Journal of medicinal chemistry
Volume	54
Issue number	24
DOIs	https://doi.org/10.1021/jm201134m
State	Published - Dec 22 2011

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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)",

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AU - Bollini, Mariela

AU - Domaoal, Robert A.

AU - Thakur, Vinay V.

AU - Gallardo-Macias, Ricardo

AU - Spasov, Krasimir A.

AU - Anderson, Karen S.

AU - Jorgensen, William L.

PY - 2011/12/22

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N2 - 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)

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

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