Targeting structural flexibility in HIV-1 protease inhibitor binding.
HIV-1 protease remains an important anti-AIDS drug target. Although it has been known that ligand binding induces large conformational changes in the protease, the dynamic aspects of binding have been largely ignored. Several computational models describing protease dynamics have been reported recently. These have reproduced experimental observations, and have also explained how ligands gain access to the binding site through dynamic behavior of the protease. Specifically, the transitions between three different conformations of the protein have been modeled in atomic detail. Two of these forms were determined by crystallography, and the third was implied by NMR experiments. Based on these computational models, it has been suggested that binding of inhibitors in allosteric sites might affect protease flexibility and disrupt its function.
Hornak
Viktor
V
Stony Brook University, Center for Structural Biology, Stony Brook, NY 11794-5155, USA.
Simmerling
Carlos
C
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D003198:Computer Simulation; D003461:Crystallography; D016503:Drug Delivery Systems; D015195:Drug Design; D024882:Drug Resistance, Viral; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation
D017320:HIV Protease Inhibitors; D008024:Ligands; D016333:HIV Protease