title: 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.
authors: Department of Medicinal Chemistry, College of Pharmacy, University of Michigan , 428 Church Street, Ann Arbor, Michigan 48109-1065, United States.
authors: Peter M-U
authors: PM
authors: Ung
authors: James B
authors: JB
authors: Dunbar
authors: Jason E
authors: JE
authors: Gestwicki
authors: Heather A
authors: HA
authors: Carlson
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry*; D024921:Drug Resistance, Multiple, Viral; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D009154:Mutation; D010436:Pepstatins / Q000737:chemistry; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry*; D054852:Small Molecule Libraries / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: C000594992:4-nitro-2-(2-thioxo-2,3-dihydrobenzothiazol-6-yl)isoindoline-1,3-dione; D052160:Benzothiazoles; D017320:HIV Protease Inhibitors; D010436:Pepstatins; D010797:Phthalimides; D054852:Small Molecule Libraries; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1; C031375:pepstatin