7TO5

HIV-1 wild type protease with GRL-05816A, with C-4 substituted cyclohexane-fused bis-tetrahydrofuran (Chf-THF) derivatives as P2-ligand [diastereomer 1]

Summary for 7TO5

• Entry DOI: 10.2210/pdb7to5/pdb
• Related: 2IEN 6BZ2 6VOD 6VOE 7TO6
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (7 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease, inhibitors, antiviral protein, antiviral protein-inhibitor complex, antiviral protein/inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22419.66

Authors

Wang, Y.-F.,Agniswamy, J.,Ghosh, A.K.,Weber, I.T. (deposition date: 2022-01-23, release date: 2022-03-02, Last modification date: 2023-10-18)

Primary citation

Ghosh, A.K.,Kovela, S.,Sharma, A.,Shahabi, D.,Ghosh, A.K.,Hopkins, D.R.,Yadav, M.,Johnson, M.E.,Agniswamy, J.,Wang, Y.F.,Hattori, S.I.,Higashi-Kuwata, N.,Aoki, M.,Amano, M.,Weber, I.T.,Mitsuya, H.
Design, Synthesis and X-Ray Structural Studies of Potent HIV-1 Protease Inhibitors Containing C-4 Substituted Tricyclic Hexahydro-Furofuran Derivatives as P2 Ligands.
Chemmedchem, 17:e202200058-e202200058, 2022

PubMed Abstract: The design, synthesis, X-ray structural, and biological evaluation of a series of highly potent HIV-1 protease inhibitors are reported herein. These inhibitors incorporate novel cyclohexane-fused tricyclic bis-tetrahydrofuran as P2 ligands in combination with a variety of P1 and P2' ligands. The inhibitor with a difluoromethylphenyl P1 ligand and a cyclopropylaminobenzothiazole P2' ligand exhibited the most potent antiviral activity. Also, it maintained potent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The corresponding inhibitor with an enantiomeric ligand was significantly less potent in these antiviral assays. The new P2 ligands were synthesized in optically active form using enzymatic desymmetrization of meso-diols as the key step. To obtain molecular insight, two high-resolution X-ray structures of inhibitor-bound HIV-1 protease were determined and structural analyses have been highlighted.

PubMed: 35170223
DOI: 10.1002/cmdc.202200058

Experimental method

X-RAY DIFFRACTION (1.13 Å)