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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

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


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.

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