title: Virtual screening, identification, and biochemical characterization of novel inhibitors of the reverse transcriptase of human immunodeficiency virus type-1.
abstract: The reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1) is a leading target in current antiretroviral therapy. Unfortunately, drug-resistant RT mutants evolve under the pressure of these drugs, and therefore, new anti-RT inhibitors are constantly required for HIV-1/AIDS treatment. We virtually screened a large chemical library of compounds against two crystal structures of HIV-1 RT to identify novel inhibitors. Top-scoring compounds were tested experimentally; 71 inhibited the RT-associated DNA polymerase, while several also inhibited HIV-1 pseudovirus infection in a cell-based assay. A combination of substituents from two structurally related inhibitors in a single molecule improved the inhibition efficacy. This compound strongly suppressed the RT-associated activity also protecting human lymphocytes from HIV-1 infection. RT inhibition by this compound was reversible and noncompetitive. This molecule and another structurally unrelated potent compound inhibited a known drug-resistant mutant of HIV-1 RT and affected moderately the HIV-2 RT-associated DNA polymerase. These inhibitors may serve as promising anti-HIV lead compounds.
authors.affiliation: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Alon
authors.initials: A
authors.lastname: Herschhorn
authors.forename: Amnon
authors.initials: A
authors.lastname: Hizi
mesh_terms: D002460:Cell Line; D018360:Crystallography, X-Ray; D024882:Drug Resistance, Viral / Q000235:genetics; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D009154:Mutation; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase