Thiocarbamates as non-nucleoside HIV-1 reverse transcriptase inhibitors: docking-based CoMFA and CoMSIA analyses

Eur J Med Chem. 2009 May;44(5):2059-70. doi: 10.1016/j.ejmech.2008.10.014. Epub 2008 Nov 1.

Abstract

Thiocarbamates (TCs) have been recently identified as a new class of potent non-nucleoside HIV-1 Reverse Transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses, has been used to elucidate the atomic details of the RT/TC interactions and to identify the most important features impacting the TC antiretroviral activity. The CoMFA model resulted to be the more predictive, and gave r(2)=0.93, r(cv)(2)=0.53, SEE=0.292, F=180, and r(test)(2)=0.70. The 3D-QSAR field contributions and the structural features of the RT binding site showed a good correlation. These studies will be useful to design new TCs with improved potency also against clinically relevant resistant mutants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computer Simulation
  • HIV Reverse Transcriptase / antagonists & inhibitors*
  • Models, Molecular
  • Protein Binding
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / pharmacology
  • Thiocarbamates / chemistry
  • Thiocarbamates / pharmacology*

Substances

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