4U8W

HIV-1 wild Type protease with GRL-050-10A (a Gem-difluoro-bis-Tetrahydrofuran as P2-Ligand)

Summary for 4U8W

• Entry DOI: 10.2210/pdb4u8w/pdb
• Related: 2IEN 3OK9 3QAA
• Descriptor: HIV-1 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, SODIUM ION, ... (6 entities in total)
• Functional Keywords: hiv-1 protease inhibitor, multidrug-resistant hiv-1 strains, blood-brain-barrier, fluoro-bis-thf, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus type 1 BH10 (HIV-1)
• Total number of polymer chains: 2
• Total formula weight: 22312.44

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2014-08-05, release date: 2014-11-05, Last modification date: 2023-09-27)

Primary citation

Ghosh, A.K.,Yashchuk, S.,Mizuno, A.,Chakraborty, N.,Agniswamy, J.,Wang, Y.F.,Aoki, M.,Gomez, P.M.,Amano, M.,Weber, I.T.,Mitsuya, H.
Design of gem-Difluoro-bis-Tetrahydrofuran as P2 Ligand for HIV-1 Protease Inhibitors to Improve Brain Penetration: Synthesis, X-ray Studies, and Biological Evaluation.
Chemmedchem, 10:107-115, 2015

PubMed Abstract: The structure-based design, synthesis, biological evaluation, and X-ray structural studies of fluorine-containing HIV-1 protease inhibitors are described. The synthesis of both enantiomers of the gem-difluoro-bis-THF ligands was carried out in a stereoselective manner using a Reformatskii-Claisen reaction as the key step. Optically active ligands were converted into protease inhibitors. Two of these inhibitors, (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-methoxyphenyl)sulfonamido)-1-phenylbutan-2-yl) carbamate (3) and (3R,3aS,6aS)-4,4-difluorohexahydrofuro[2,3-b]furan-3-yl(2S,3R)-3-hydroxy-4-((N-isobutyl-4-aminophenyl)sulfonamido)phenylbutan-2-yl) carbamate (4), exhibited HIV-1 protease inhibitory Ki values in the picomolar range. Both 3 and 4 showed very potent antiviral activity, with respective EC50 values of 0.8 and 3.1 nM against the laboratory strain HIV-1LAI . The two inhibitors exhibited better lipophilicity profiles than darunavir, and also showed much improved blood-brain barrier permeability in an in vitro model. A high-resolution X-ray structure of inhibitor 4 in complex with HIV-1 protease was determined, revealing that the fluorinated ligand makes extensive interactions with the S2 subsite of HIV-1 protease, including hydrogen bonding interactions with the protease backbone atoms. Moreover, both fluorine atoms on the bis-THF ligand formed strong interactions with the flap Gly 48 carbonyl oxygen atom.

PubMed: 25336073
DOI: 10.1002/cmdc.201402358

Experimental method

X-RAY DIFFRACTION (1.3 Å)