Structural and energetic analyses of the effects of the K103N mutation of HIV-1 reverse transcriptase on efavirenz analogues

J Med Chem. 2004 Apr 22;47(9):2389-92. doi: 10.1021/jm0303507.

Abstract

The effect of the K103N mutation of HIV-1 reverse transcriptase (RT) on the activity of efavirenz analogues was studied via Monte Carlo/free energy perturbation calculations. The relative fold resistance energies indicate that efavirenz binds to K103N RT in a manner similar to the wild-type enzyme. The improved performance of the quinazolinones against the mutant enzyme is attributed to formation of a more optimal hydrogen-bonding network with bridging water molecules between the ligands and Glu138.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics*
  • Models, Molecular
  • Monte Carlo Method
  • Mutation
  • Oxazines / chemistry*
  • Protein Binding
  • Reverse Transcriptase Inhibitors / chemistry*
  • Thermodynamics

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Oxazines
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase
  • efavirenz

Associated data

  • PDB/1FKO
  • PDB/1IKV
  • PDB/1RT3
  • PDB/1RTI