Solution Kinetics Measurements Suggest HIV-1 Protease Has Two Binding Sites for Darunavir and Amprenavir
- 20 September 2008
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 51 (20), 6599-6603
- https://doi.org/10.1021/jm800283k
Abstract
Darunavir, a potent antiviral drug, showed an unusual second binding site on the HIV-1 protease dimer surface of the V32I drug resistant mutant and normal binding in the active site cavity. Kinetic analysis for wild type and mutant protease showed mixed-type competitive-uncompetitive inhibition for darunavir and the chemically related amprenavir, while saquinavir showed competitive inhibition. The inhibition model is consistent with the observed second binding site for darunavir and helps to explain its antiviral potency.Keywords
This publication has 28 references indexed in Scilit:
- Binding Kinetics of Darunavir to Human Immunodeficiency Virus Type 1 Protease Explain the Potent Antiviral Activity and High Genetic BarrierJournal of Virology, 2007
- Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1AIDS, 2007
- Ultra-high Resolution Crystal Structure of HIV-1 Protease Mutant Reveals Two Binding Sites for Clinical Inhibitor TMC114Journal of Molecular Biology, 2006
- Beta-lactam compounds as apparently uncompetitive inhibitors of HIV-1 proteaseBioorganic & Medicinal Chemistry Letters, 2005
- High Resolution Crystal Structures of HIV-1 Protease with a Potent Non-peptide Inhibitor (UIC-94017) Active Against Multi-drug-resistant Clinical StrainsJournal of Molecular Biology, 2004
- Crystal structure of HIV-1 protease in complex with VX-478, a potent and orally bioavailable inhibitor of the enzymeJournal of the American Chemical Society, 1995
- Rational Design of Potent, Bioavailable, Nonpeptide Cyclic Ureas as HIV Protease InhibitorsScience, 1994
- Structure of Complex of Synthetic HIV-1 Protease with a Substrate-Based Inhibitor at 2.3 Å ResolutionScience, 1989
- Inhibition of porcine pepsin by two substrate analogs containing statine. The effect of histidine at the P2 subsite on the inhibition of aspartic proteinasesJournal of Medicinal Chemistry, 1988
- Why is uncompetitive inhibition so rare?FEBS Letters, 1986