De novo parallel design, synthesis and evaluation of inhibitors against the reverse transcriptase of human immunodeficiency virus type-1 and drug-resistant variants

Alon Herschhorn, Lena Lerman, Michal Weitman, Iris Oz Gleenberg, Abraham Nudelman, Amnon Hizi

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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 μM. Compound 5f inhibited RT with an IC50 value of about 3.5 μM, 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 μM 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.

Original languageEnglish (US)
Pages (from-to)2370-2384
Number of pages15
JournalJournal of medicinal chemistry
Volume50
Issue number10
DOIs
StatePublished - May 17 2007

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