Crystallography and the design of anti-AIDS drugs: conformational flexibility and positional adaptability are important in the design of non-nucleoside HIV-1 reverse transcriptase inhibitors

Prog Biophys Mol Biol. 2005 Jun;88(2):209-31. doi: 10.1016/j.pbiomolbio.2004.07.001.


Drug resistance is a key cause of failure for treatment of HIV infection. The efficacy of non-nucleoside reverse transcriptase inhibiting (NNRTI) drugs is impaired by rapid emergence of drug-resistance mutations. A multidisciplinary effort led to the discovery of the potent NNRTIs dapivirine and etravirine, both of which are diarylpyrimidine (DAPY) derivatives. Systematic structural and molecular modeling studies of HIV-1 reverse transcriptase (RT)/NNRTI complexes revealed different modes of inhibitor binding, and some of the DAPY inhibitors can bind to RT in different conformations. The torsional flexibility ("wiggling") of the inhibitors can generate numerous conformational variants and the compactness of the inhibitors permits significant repositioning and reorientation (translation and rotation) within the pocket ("jiggling"). Such adaptations appear to be critical for the ability of the diarylpyrimidine NNRTIs to retain their potency against a wide range of drug-resistant HIV-1 RTs. Exploitation of inhibitor conformational flexibility (such as torsional flexibility about strategically located chemical bonds) can be a powerful element of drug design, especially for the design of drugs that will be effective against rapidly mutating targets (which is a collection of related targets).

Publication types

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

MeSH terms

  • Acquired Immunodeficiency Syndrome / drug therapy
  • Acquired Immunodeficiency Syndrome / virology
  • Adaptation, Physiological
  • Animals
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / chemistry
  • Crystallography / methods*
  • Drug Delivery Systems / methods
  • Drug Design*
  • Drug Resistance, Multiple, Viral / genetics
  • Gene Expression Regulation, Viral / physiology
  • Genetic Variation
  • HIV Reverse Transcriptase / chemistry*
  • HIV Reverse Transcriptase / genetics
  • HIV Reverse Transcriptase / metabolism*
  • HIV-1 / drug effects*
  • HIV-1 / enzymology*
  • HIV-1 / genetics
  • Humans
  • Protein Conformation
  • Reverse Transcriptase Inhibitors / administration & dosage
  • Reverse Transcriptase Inhibitors / chemistry*
  • Structure-Activity Relationship


  • Anti-HIV Agents
  • Reverse Transcriptase Inhibitors
  • HIV Reverse Transcriptase