6E9A

HIV-1 WILD TYPE PROTEASE WITH GRL-034-17A, (3aS, 5R, 6aR)-2-OXOHEXAHYD CYCLOPENTA[D]-5-OXAZOLYL URETHANE WITH A BICYCLIC OXAZOLIDINONE SCAFF AS THE P2 LIGAND

Summary for 6E9A

• Entry DOI: 10.2210/pdb6e9a/pdb
• Related: 2IEN 6E7J
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (6 entities in total)
• Functional Keywords: antiviral, hiv-1 protease inhibitor of grl-034-17a, p2 ligand, multidrug-resistant, oxazolidinone, viral protein, hydrolase-hydrolase inhibitor complex, hydrolase, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22219.94

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2018-07-31, release date: 2018-11-07, Last modification date: 2023-10-11)

Primary citation

Ghosh, A.K.,Williams, J.N.,Ho, R.Y.,Simpson, H.M.,Hattori, S.I.,Hayashi, H.,Agniswamy, J.,Wang, Y.F.,Weber, I.T.,Mitsuya, H.
Design and Synthesis of Potent HIV-1 Protease Inhibitors Containing Bicyclic Oxazolidinone Scaffold as the P2 Ligands: Structure-Activity Studies and Biological and X-ray Structural Studies.
J. Med. Chem., 61:9722-9737, 2018

PubMed Abstract: We have designed, synthesized, and evaluated a new class of potent HIV-1 protease inhibitors with novel bicyclic oxazolidinone derivatives as the P2 ligand. We have developed an enantioselective synthesis of these bicyclic oxazolidinones utilizing a key o-iodoxybenzoic acid mediated cyclization. Several inhibitors displayed good to excellent activity toward HIV-1 protease and significant antiviral activity in MT-4 cells. Compound 4k has shown an enzyme K of 40 pM and antiviral IC of 31 nM. Inhibitors 4k and 4l were evaluated against a panel of highly resistant multidrug-resistant HIV-1 variants, and their fold-changes in antiviral activity were similar to those observed with darunavir. Additionally, two X-ray crystal structures of the related inhibitors 4a and 4e bound to HIV-1 protease were determined at 1.22 and 1.30 Å resolution, respectively, and revealed important interactions in the active site that have not yet been explored.

PubMed: 30354121
DOI: 10.1021/acs.jmedchem.8b01227

Experimental method

X-RAY DIFFRACTION (1.22 Å)