6VOD

HIV-1 wild type protease with GRL-052-16A, a tricyclic cyclohexane fused tetrahydrofuranofuran (CHf-THF) derivative as the P2 ligand

Summary for 6VOD

• Entry DOI: 10.2210/pdb6vod/pdb
• Related: 2IEN 5ULT 6BZ2 6CDJ 6CDL 6VOE
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: inhibitors, antiviral, multidrug-resistant, chf-thf, backbone binding, antiviral protein
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22302.08

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2020-01-30, release date: 2020-05-13, Last modification date: 2023-10-11)

Primary citation

Ghosh, A.K.,Kovela, S.,Osswald, H.L.,Amano, M.,Aoki, M.,Agniswamy, J.,Wang, Y.F.,Weber, I.T.,Mitsuya, H.
Structure-Based Design of Highly Potent HIV-1 Protease Inhibitors Containing New Tricyclic Ring P2-Ligands: Design, Synthesis, Biological, and X-ray Structural Studies.
J.Med.Chem., 63:4867-4879, 2020

PubMed Abstract: We describe here design, synthesis, and biological evaluation of a series of highly potent HIV-1 protease inhibitors containing stereochemically defined and unprecedented tricyclic furanofuran derivatives as P2 ligands in combination with a variety of sulfonamide derivatives as P2' ligands. These inhibitors were designed to enhance the ligand-backbone binding and van der Waals interactions in the protease active site. A number of inhibitors containing the new P2 ligand, an aminobenzothiazole as the P2' ligand and a difluorophenylmethyl as the P1 ligand, displayed very potent enzyme inhibitory potency and also showed excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The tricyclic P2 ligand has been synthesized efficiently in an optically active form using enzymatic desymmetrization of meso-1,2-(dihydroxymethyl)cyclohex-4-ene as the key step. We determined high-resolution X-ray structures of inhibitor-bound HIV-1 protease. These structures revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insights into the binding properties of these new inhibitors.

PubMed: 32348139
DOI: 10.1021/acs.jmedchem.0c00202

Experimental method

X-RAY DIFFRACTION (1.25 Å)