Affordable Access

Modelling the binding of HIV-reverse transcriptase and nevirapine: an assessment of quantum mechanical and force field approaches and predictions of the effect of mutations on binding

Authors
Journal
Physical Chemistry Chemical Physics
1463-9076
Publisher
The Royal Society of Chemistry
Publication Date
Keywords
  • Nonnucleoside Inhibitors
  • Noncovalent Interactions
  • Drug-Resistance
  • Thermochemical Kinetics
  • Density Functionals
  • Molecular-Mechanics
  • Dispersion Corrections
  • Free-Energies
  • Liquid Water
  • Oniom Method
Disciplines
  • Computer Science
  • Physics

Abstract

The importance of the intermolecular interactions which contribute to the binding of HIV-1 RT with the NNRTI inhibitor, nevirapine (NVP), has been studied using quantum mechanical and molecular simulation methods. A range of computational methods, including density functional theory with empirical dispersion corrections, have been employed and show that although pi-pi stacking interactions are important, the combined effect of a number of C-H/pi interactions provides a significant contribution to the binding. The AMBER empirical force-field has been shown to be particularly effective to describe the interactions in this case; MM-GBSA free-energy methods were subsequently used to explore the effects on binding with several known mutations of HIV-1 RT. The relative affinities from the mutation simulations are shown to be in good agreement with experimental data allowing the causes of the binding changes to be discussed.

There are no comments yet on this publication. Be the first to share your thoughts.