Solvation effects are responsible for the reduced inhibitor affinity of some HIV-1 PR mutants.
The formulation of HIV-1 PR inhibitors as anti-viral drugs has been hindered by the appearance of protease strains that present drug resistance to these compounds. The mechanism by which the HIV-1 PR mutants lower their affinity for the inhibitor is not yet fully understood. We have applied a modified Poisson-Boltzmann method to the evaluation of the molecular interactions that contribute to the lowering of the inhibitor affinity to some polar mutants at position 82. These strains present drug resistance behavior and hence are ideally suited for these studies. Our results indicate that the reduction in binding affinity is due to the solvation effects that penalize the binding to the more polar mutants. The inhibitor binding ranking of the different mutants can be explained from the analysis of the different components of our free energy scoring function.
Sussman
F
F
Oklahoma University, Health Sciences Center, Oklahoma City 73104, USA. fredy@rev.uokhsc.edu
Villaverde
M C
MC
Davis
A
A
D001120:Arginine; D001665:Binding Sites; D018698:Glutamic Acid; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012996:Solutions; D013816:Thermodynamics
D017320:HIV Protease Inhibitors; D011994:Recombinant Proteins; D012996:Solutions; D018698:Glutamic Acid; D001120:Arginine; D016333:HIV Protease