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Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures.

ABSTRACT: To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercially available compounds. Two of the structures are for WT-virus with different conformations of Tyr181, while the third structure incorporates the Y181C modification. Eventually nine compounds were purchased and assayed. Three of the compounds show low-micromolar antiviral activity toward either or both the wild-type and Y181C HIV-1 strains. The study illustrates a viable protocol to seek anti-HIV agents with enhanced resistance profiles.

SUBMITTER: Nichols SE

PROVIDER: S-EPMC2817966 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures.

Nichols Sara E SE Domaoal Robert A RA Thakur Vinay V VV Tirado-Rives Julian J Anderson Karen S KS Jorgensen William L WL

Journal of chemical information and modeling 20090501 5

To discover non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) that are effective against both wild-type (WT) virus and variants that encode the clinically troublesome Tyr181Cys (Y181C) RT mutation, virtual screening by docking was carried out using three RT structures and more than 2 million commercially available compounds. Two of the structures are for WT-virus with different conformations of Tyr181, while the third structure incorporates the Y181C modification. Eventually nine ...[more]

PMID: 19374380

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