5BRY

HIV-1 wild Type protease with GRL-011-11A (a methylamine bis-Tetrahydrofuran P2-Ligand, sulfonamide isostere derivate)

Summary for 5BRY

• Entry DOI: 10.2210/pdb5bry/pdb
• Related: 2IEN 3QAA 5BS4
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: 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: 22225.41

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2015-06-01, release date: 2015-09-09, Last modification date: 2023-09-27)

Primary citation

Ghosh, A.K.,Martyr, C.D.,Osswald, H.L.,Sheri, V.R.,Kassekert, L.A.,Chen, S.,Agniswamy, J.,Wang, Y.F.,Hayashi, H.,Aoki, M.,Weber, I.T.,Mitsuya, H.
Design of HIV-1 Protease Inhibitors with Amino-bis-tetrahydrofuran Derivatives as P2-Ligands to Enhance Backbone-Binding Interactions: Synthesis, Biological Evaluation, and Protein-Ligand X-ray Studies.
J.Med.Chem., 58:6994-7006, 2015

PubMed Abstract: Structure-based design, synthesis, and biological evaluation of a series of very potent HIV-1 protease inhibitors are described. In an effort to improve backbone ligand-binding site interactions, we have incorporated basic-amines at the C4 position of the bis-tetrahydrofuran (bis-THF) ring. We speculated that these substituents would make hydrogen bonding interactions in the flap region of HIV-1 protease. Synthesis of these inhibitors was performed diastereoselectively. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 25f, 25i, and 25j were evaluated against a number of highly-PI-resistant HIV-1 strains, and they exhibited improved antiviral activity over darunavir. Two high resolution X-ray structures of 25f- and 25g-bound HIV-1 protease revealed unique hydrogen bonding interactions with the backbone carbonyl group of Gly48 as well as with the backbone NH of Gly48 in the flap region of the enzyme active site. These ligand-binding site interactions are possibly responsible for their potent activity.

PubMed: 26306007
DOI: 10.1021/acs.jmedchem.5b00900

Experimental method

X-RAY DIFFRACTION (1.34 Å)