title: De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants.
abstract: We used molecular modeling to design de novo broad-range inhibitors against wild type and drug-resistant variants of the reverse transcriptase (RT) of human immunodeficiency virus type-1 (HIV-1). First, we screened for small fragments that would interact with each one of four RT structures (one wild type and three mutants). Then, these fragments were linked to build a scaffold molecule. Out of 27 different compounds that were synthesized, four inhibited the DNA polymerase activity of RT with IC50 values below 10 microM. Compound 5f inhibited RT with an IC50 value of about 3.5 microM, while inhibiting drug-resistant RT variants more efficiently than the clinically used drug, nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one). 5f also inhibited the RT ribonuclease H activity with an IC50 of 20 microM and therefore, unlike nevirapine, targets both RT activities. Accordingly, 5f can serve as lead for developing novel inhibitors against RT that may be used to suppress HIV-1 growth.
authors: Department of Cell and Developmental Biology, Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors: Alon
authors: A
authors: Herschhorn
authors: Lena
authors: L
authors: Lerman
authors: Michal
authors: M
authors: Weitman
authors: Iris Oz
authors: IO
authors: Gleenberg
authors: Abraham
authors: A
authors: Nudelman
authors: Amnon
authors: A
authors: Hizi
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D002074:Butanones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D015195:Drug Design; D024882:Drug Resistance, Viral; D054303:HIV Reverse Transcriptase / Q000737:chemistry*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D019829:Nevirapine / Q000737:chemistry; D009570:Nitriles / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D019384:Nucleic Acid Synthesis Inhibitors; D011487:Protein Conformation; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D016914:Ribonuclease H / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C520856:4-(3-iodophenyl)-3-oxobutanenitrile; D019380:Anti-HIV Agents; D002074:Butanones; D009570:Nitriles; D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019829:Nevirapine; D054303:HIV Reverse Transcriptase; D004259:DNA-Directed DNA Polymerase; D016914:Ribonuclease H