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

J Med Chem. 2007 May 17;50(10):2370-84. doi: 10.1021/jm0613121. Epub 2007 Apr 26.

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.

MeSH terms

  • Animals
  • Anti-HIV Agents / chemical synthesis*
  • Anti-HIV Agents / chemistry
  • Anti-HIV Agents / toxicity
  • Binding Sites
  • Butanones / chemical synthesis*
  • Butanones / chemistry
  • Butanones / toxicity
  • DNA-Directed DNA Polymerase / chemistry
  • Drug Design
  • Drug Resistance, Viral*
  • HIV Reverse Transcriptase / chemistry*
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • In Vitro Techniques
  • Mice
  • Models, Molecular
  • Nevirapine / chemistry
  • Nitriles / chemical synthesis*
  • Nitriles / chemistry
  • Nitriles / toxicity
  • Nucleic Acid Synthesis Inhibitors
  • Protein Conformation
  • Reverse Transcriptase Inhibitors / chemical synthesis*
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / toxicity
  • Ribonuclease H / antagonists & inhibitors
  • Ribonuclease H / chemistry
  • Structure-Activity Relationship

Substances

  • 4-(3-iodophenyl)-3-oxobutanenitrile
  • Anti-HIV Agents
  • Butanones
  • Nitriles
  • Nucleic Acid Synthesis Inhibitors
  • Reverse Transcriptase Inhibitors
  • Nevirapine
  • HIV Reverse Transcriptase
  • DNA-Directed DNA Polymerase
  • Ribonuclease H