2008
DOI: 10.1021/jm800283k
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Solution Kinetics Measurements Suggest HIV-1 Protease Has Two Binding Sites for Darunavir and Amprenavir

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 antivi… Show more

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Cited by 30 publications
(31 citation statements)
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“…The crystal structure of GRL-216 revealed that, as in the case of DRV (16,25), the bis-THF moiety of GRL-216 forms strong hydrogen-bonding interactions with the backbones of D29 and D30 of protease and the compound has good interactions with D25 and I50, which should give GRL-216 significantly potent activity against diverse wild-type and multidrugresistant HIV-1 strains. However, the macrocyclic ring was found to occupy more of the binding cavity of protease and form more van der Waals interactions with V82 and I84 than the corresponding isopropyl group of DRV ( Fig.…”
Section: Discussionmentioning
confidence: 99%
“…The crystal structure of GRL-216 revealed that, as in the case of DRV (16,25), the bis-THF moiety of GRL-216 forms strong hydrogen-bonding interactions with the backbones of D29 and D30 of protease and the compound has good interactions with D25 and I50, which should give GRL-216 significantly potent activity against diverse wild-type and multidrugresistant HIV-1 strains. However, the macrocyclic ring was found to occupy more of the binding cavity of protease and form more van der Waals interactions with V82 and I84 than the corresponding isopropyl group of DRV ( Fig.…”
Section: Discussionmentioning
confidence: 99%
“…In addition, the extreme efficacy of DRV was also attributed to the following observations. (i) Crystal structures revealed that DRV not only binds to the active site but also occupies a surface pocket formed by one of the HIV-1 PR flaps, and enzyme kinetic analysis confirmed that DRV has a second binding site (37,38); and (ii) a FRET assay suggested that DRV has a dual mechanism of inhibition, as it might also be a potential HIV-1 PR dimerization inhibitor (39,40). Our previous studies demonstrated that TL-3 is potent and has a very narrow range of IC 50 s for WT FIV and chimeric mutants (21,22,24).…”
Section: Fig 5 Western Blot Analysis Of Gag Processing By 6s-98s and mentioning
confidence: 95%
“…40) may relate to an allosteric interaction that could contribute to the inhibition of HIV PR and therefore be partially responsible for DRV's enhanced potency. Furthermore, kinetic studies performed with DRV and APV have revealed a mixed-type competitive-uncompetitive inhibition against HIV PR in contrast to other PIs like SQV that operate purely by competitive inhibition [188]. Interestingly, two distinct diastereomers of DRV related by inversion of the sulfonamide nitrogen were found to bind at the two different sites.…”
Section: Binding Interactionsmentioning
confidence: 99%
“…Subsequent X-ray analysis of DRV complexed with HIV PR mutants has revealed a second binding site for DRV on one of the flexible flaps located on the surface of the protease (see Fig. 39) [95,186,188]. Binding at this site (see Fig.…”
Section: Binding Interactionsmentioning
confidence: 99%
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