Crystal structures of HIV-1 reverse transcriptase complexes with thiocarbamate non-nucleoside inhibitors

Biochem Biophys Res Commun. 2008 Jan 25;365(4):764-70. doi: 10.1016/j.bbrc.2007.11.036. Epub 2007 Nov 21.

Abstract

O-Phthalimidoethyl-N-arylthiocarbamates (TCs) have been recently identified as a new class of potent HIV-1 reverse transcriptase (RT) non-nucleoside inhibitors (NNRTIs), by means of computer-aided drug design techniques [Ranise A. Spallarossa, S. Cesarini, F. Bondavalli, S. Schenone, O. Bruno, G. Menozzi, P. Fossa, L. Mosti, M. La Colla, et al., Structure-based design, parallel synthesis, structure-activity relationship, and molecular modeling studies of thiocarbamates, new potent non-nucleoside HIV-1 reverse transcriptase inhibitor isosteres of phenethylthiazolylthiourea derivatives, J. Med. Chem. 48 (2005) 3858-3873]. To elucidate the atomic details of RT/TC interaction and validate an earlier TC docking model, the structures of three RT/TC complexes were determined at 2.8-3.0A resolution by X-ray crystallography. The conformations adopted by the enzyme-bound TCs were analyzed and compared with those of bioisosterically related NNRTIs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Crystallography / methods
  • Enzyme Activation
  • Enzyme Inhibitors / chemistry
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / ultrastructure*
  • Models, Chemical*
  • Models, Molecular*
  • Nucleosides / chemistry
  • Protein Binding
  • Protein Conformation
  • Thiocarbamates / chemistry*

Substances

  • Enzyme Inhibitors
  • Nucleosides
  • Thiocarbamates
  • reverse transcriptase, Human immunodeficiency virus 1
  • HIV Reverse Transcriptase