Discovery of wild-type and Y181C mutant non-nucleoside HIV-1 reverse transcriptase inhibitors using virtual screening with multiple protein structures.
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.
Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut 06511, USA.
Sara E
SE
Nichols
Robert A
RA
Domaoal
Vinay V
VV
Thakur
Julian
J
Tirado-Rives
Karen S
KS
Anderson
William L
WL
Jorgensen
D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology
D018894:Reverse Transcriptase Inhibitors