4YHQ

Crystal structure of multidrug resistant clinical isolate PR20 with GRL-5010A

Summary for 4YHQ

• Entry DOI: 10.2210/pdb4yhq/pdb
• Descriptor: Protease, (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl](2-methylpropyl)amino}-3-hydroxy-1-phenylbutan-2-yl]carbamate, YTTRIUM ION, ... (7 entities in total)
• Functional Keywords: hiv protease, mutant, drug resistant, inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 group M subtype (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 22856.80

Authors

Agniswamy, J.,Weber, I.T. (deposition date: 2015-02-27, release date: 2015-06-10, Last modification date: 2023-09-27)

Primary citation

Agniswamy, J.,Louis, J.M.,Shen, C.H.,Yashchuk, S.,Ghosh, A.K.,Weber, I.T.
Substituted Bis-THF Protease Inhibitors with Improved Potency against Highly Resistant Mature HIV-1 Protease PR20.
J.Med.Chem., 58:5088-5095, 2015

PubMed Abstract: An extremely drug resistant mutant of HIV-1 protease (PR) bearing 20 mutations (PR20) has been studied with two potent antiviral investigational inhibitors. GRL-5010A and GRL-4410A were designed to introduce hydrogen bond interactions with the flexible flaps of the PR by incorporating gem-difluorines and alkoxy, respectively, at the C4 position of the bis-THF of darunavir. PR20 provides an excellent model for high level resistance, since clinical inhibitors are >1000-fold less active on PR20 than on wild-type enzyme. GRL-5010A and GRL-4410A show inhibition constants of 4.3 ± 7.0 and 1.7 ± 1.8 nM, respectively, for PR20, compared to the binding affinity of 41 ± 1 nM measured for darunavir. Crystal structures of PR20 in complexes with the two inhibitors confirmed the new hydrogen bond interactions with Gly 48 in the flap of the enzyme. The two new compounds are more effective than darunavir in inhibiting mature PR20 and show promise for further development of antiviral agents targeting highly resistant PR mutants.

PubMed: 26010498
DOI: 10.1021/acs.jmedchem.5b00474

Experimental method

X-RAY DIFFRACTION (1.3 Å)