Solution Kinetics Measurements Suggest HIV-1 Protease Has Two Binding Sites for Darunavir and Amprenavir
نویسندگان
چکیده
منابع مشابه
Structural and thermodynamic basis of amprenavir/darunavir and atazanavir resistance in HIV-1 protease with mutations at residue 50.
Drug resistance occurs through a series of subtle changes that maintain substrate recognition but no longer permit inhibitor binding. In HIV-1 protease, mutations at I50 are associated with such subtle changes that confer differential resistance to specific inhibitors. Residue I50 is located at the protease flap tips, closing the active site upon ligand binding. Under selective drug pressure, I...
متن کاملEffects of drug-resistant mutations on the dynamic properties of HIV-1 protease and inhibition by Amprenavir and Darunavir
Molecular dynamics simulations are performed to investigate the dynamic properties of wild-type HIV-1 protease and its two multi-drug-resistant variants (Flap + (L10I/G48V/I54V/V82A) and Act (V82T/I84V)) as well as their binding with APV and DRV inhibitors. The hydrophobic interactions between flap and 80 s (80's) loop residues (mainly I50-I84' and I50'-I84) play an important role in maintainin...
متن کاملHow Does Darunavir Prevent HIV-1 Protease Dimerization?
The drug Darunavir (DRV) is a potent inhibitor of HIV-1 protease (PR), a homodimeric essential enzyme of the AIDS virus. Recent experimental data suggest that DRV is able to prevent dimerization of HIV-1 PR, which, together with its high affinity for the mature enzyme, has been linked to the high genetic barrier to the development of viral resistance. The mechanism of dimerization inhibition an...
متن کاملStructures of Darunavir-Resistant HIV-1 Protease Mutant Reveal Atypical Binding of Darunavir to Wide Open Flaps
The molecular basis for high resistance to clinical inhibitors of HIV-1 protease (PR) was examined for the variant designated PRP51 that was selected for resistance to darunavir (DRV). High resolution crystal structures of PRP51 with the active site D25N mutation revealed a ligand-free form and an inhibitor-bound form showing a unique binding site and orientation for DRV. This inactivating muta...
متن کاملRevealing Origin of Decrease in Potency of Darunavir and Amprenavir against HIV-2 relative to HIV-1 Protease by Molecular Dynamics Simulations
Clinical inhibitors Darunavir (DRV) and Amprenavir (APV) are less effective on HIV-2 protease (PR2) than on HIV-1 protease (PR1). To identify molecular basis associated with the lower inhibition, molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations were performed to investigate the effectiveness of the PR1 inhibitors DRV and APV again...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: Journal of Medicinal Chemistry
سال: 2008
ISSN: 0022-2623,1520-4804
DOI: 10.1021/jm800283k