Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase

J Med Chem. 2009 Oct 22;52(20):6467-73. doi: 10.1021/jm901167t.


Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC(50) </= 1 nM). ADAM 4 was designed to be hydrolytically stable in blood plasma, and an investigation of its hydrolysis in rat plasma demonstrated it has a significantly prolonged half-life in comparison to ADAM lead compounds 1 and 2.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • HIV Reverse Transcriptase / chemistry
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • HIV-1 / enzymology*
  • Humans
  • Hydrolysis
  • Inhibitory Concentration 50
  • Methane / blood
  • Methane / chemistry
  • Methane / metabolism*
  • Methane / pharmacology*
  • Models, Molecular
  • Protein Binding
  • Protein Structure, Tertiary
  • Rats
  • Reverse Transcriptase Inhibitors / blood
  • Reverse Transcriptase Inhibitors / chemistry
  • Reverse Transcriptase Inhibitors / metabolism*
  • Reverse Transcriptase Inhibitors / pharmacology*


  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • Methane

Associated data

  • PDB/3IRX
  • PDB/3IS9