Unknown

Dataset Information

0

An allosteric modulator of HIV-1 protease shows equipotent inhibition of wild-type and drug-resistant proteases.


ABSTRACT: NMR and MD simulations have demonstrated that the flaps of HIV-1 protease (HIV-1p) adopt a range of conformations that are coupled with its enzymatic activity. Previously, a model was created for an allosteric site located between the flap and the core of HIV-1p, called the Eye site (Biopolymers 2008, 89, 643-652). Here, results from our first study were combined with a ligand-based, lead-hopping method to identify a novel compound (NIT). NIT inhibits HIV-1p, independent of the presence of an active-site inhibitor such as pepstatin A. Assays showed that NIT acts on an allosteric site other than the dimerization interface. MD simulations of the ligand-protein complex show that NIT stably binds in the Eye site and restricts the flaps. That bound state of NIT is consistent with a crystal structure of similar fragments bound in the Eye site (Chem. Biol. Drug Des. 2010, 75, 257-268). Most importantly, NIT is equally potent against wild-type and a multidrug-resistant mutant of HIV-1p, which highlights the promise of allosteric inhibitors circumventing existing clinical resistance.

SUBMITTER: Ung PM 

PROVIDER: S-EPMC4136727 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

altmetric image

Publications

An allosteric modulator of HIV-1 protease shows equipotent inhibition of wild-type and drug-resistant proteases.

Ung Peter M-U PM   Dunbar James B JB   Gestwicki Jason E JE   Carlson Heather A HA  

Journal of medicinal chemistry 20140801 15


NMR and MD simulations have demonstrated that the flaps of HIV-1 protease (HIV-1p) adopt a range of conformations that are coupled with its enzymatic activity. Previously, a model was created for an allosteric site located between the flap and the core of HIV-1p, called the Eye site (Biopolymers 2008, 89, 643-652). Here, results from our first study were combined with a ligand-based, lead-hopping method to identify a novel compound (NIT). NIT inhibits HIV-1p, independent of the presence of an ac  ...[more]

Similar Datasets

| S-EPMC2751596 | biostudies-literature
| S-EPMC4521605 | biostudies-literature
| S-EPMC4108181 | biostudies-literature
| S-EPMC6545544 | biostudies-literature
| S-EPMC6501176 | biostudies-literature
| S-EPMC8432871 | biostudies-literature
| S-EPMC4823711 | biostudies-literature
| S-EPMC6618080 | biostudies-literature
| S-EPMC3923078 | biostudies-literature
| S-EPMC2144243 | biostudies-other