title: Discovery of novel inhibitors of HIV-1 reverse transcriptase through virtual screening of experimental and theoretical ensembles.
abstract: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are potent anti-HIV chemotherapeutics. Although there are FDA-approved NNRTIs, challenges such as the development of resistance have limited their utility. Here, we describe the identification of novel NNRTIs through a combination of computational and experimental approaches. Based on the known plasticity of the NNRTI binding pocket (NNIBP), we adopted an ensemble-based virtual screening strategy: coupling receptor conformations from 10 X-ray crystal structures with 120 snapshots from a total of 480 ns of molecular dynamics (MD) trajectories. A screening library of 2864 National Cancer Institute (NCI) compounds was built and docked against the ensembles in a hierarchical fashion. Sixteen diverse compounds were tested for their ability to block HIV infection in human tissue cultures using a luciferase-based reporter assay. Three promising compounds were further characterized, using a HIV-1 RT-based polymerase assay, to determine the specific mechanism of inhibition. We found that 2 of the three compounds inhibited the polymerase activity of RT (with potency similar to the positive control, the FDA-approved drug nevirapine). Through a computational approach, we were able to discover two compounds which inhibit HIV replication and block the activity of RT, thus offering the potential for optimization into mature inhibitors.
authors.affiliation: Department of Chemistry and Biochemistry, University of California at San Diego, La Jolla, CA, 92093-0365, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Ivetac
authors.forename: Sara E
authors.initials: SE
authors.lastname: Swift
authors.forename: Paul L
authors.initials: PL
authors.lastname: Boyer
authors.forename: Arturo
authors.initials: A
authors.lastname: Diaz
authors.forename: John
authors.initials: J
authors.lastname: Naughton
authors.forename: John A T
authors.initials: JA
authors.lastname: Young
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Hughes
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D001665:Binding Sites; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D056004:Molecular Dynamics Simulation; D017434:Protein Structure, Tertiary; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D018894:Reverse Transcriptase Inhibitors; D054852:Small Molecule Libraries; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase
keywords: HIV; NNRTI; molecular dynamics; reverse transcriptase; virtual screening