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

J Mol Model. 2009 Jul;15(7):871-84. doi: 10.1007/s00894-008-0441-6. Epub 2009 Jan 20.

Abstract

Acylthiocarbamates (ATCs) have been identified as a class of potent non-nucleoside HIV-1 reverse transcriptase (RT) inhibitors. A computational strategy based on molecular docking studies followed by comparative molecular fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) was used to identify the most important features impacting ATC antiretroviral activity. The CoMSIA model proved to be the more predictive, with r(2)(ncv) = 0.89, r(cv)(2) = 0.38, standard error of estimate (SEE) = 0.494, F = 84, and r(2)(pred) = 0.81. The results of these studies will be useful in designing new ATCs with improved potency, also against clinically relevant resistant mutants.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Binding Sites
  • Computer Simulation
  • Crystallography, X-Ray
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / drug effects
  • Humans
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Models, Molecular
  • Molecular Structure
  • Protein Binding
  • Protein Structure, Tertiary
  • Quantitative Structure-Activity Relationship
  • Reverse Transcriptase Inhibitors / chemistry*
  • Reverse Transcriptase Inhibitors / metabolism
  • Reverse Transcriptase Inhibitors / pharmacology
  • Static Electricity
  • Thiocarbamates / chemistry*
  • Thiocarbamates / metabolism
  • Thiocarbamates / pharmacology

Substances

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