6CDJ

HIV-1 wild type protease with GRL-03314A, 6-5-5-ring fused umbrella-like tetrahydropyranofuran as the P2-ligand, a cyclopropylaminobenzothiazole as the P2'-ligand and 3,5-difluorophenylmethyl as the P1-ligand

Summary for 6CDJ

• Entry DOI: 10.2210/pdb6cdj/pdb
• Related: 2IEN 6BZ2
• Descriptor: Protease, (2aS,4R,4aS,7aS,7bS)-octahydro-2H-1,7-dioxacyclopenta[cd]inden-4-yl [(2S,3R)-4-[{[2-(cyclopropylamino)-1,3-benzothiazol-6-yl]sulfonyl}(2-methylpropyl)amino]-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]carbamate, SODIUM ION, ... (7 entities in total)
• Functional Keywords: aspartic acid protease, hiv-1 protease inhibitor of grl-03314a, umb-thf, antiviral, multidrug-resistant, synthesis, backbone binding, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22541.73

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2018-02-08, release date: 2018-05-30, Last modification date: 2023-10-04)

Primary citation

Ghosh, A.K.,R Nyalapatla, P.,Kovela, S.,Rao, K.V.,Brindisi, M.,Osswald, H.L.,Amano, M.,Aoki, M.,Agniswamy, J.,Wang, Y.F.,Weber, I.T.,Mitsuya, H.
Design and Synthesis of Highly Potent HIV-1 Protease Inhibitors Containing Tricyclic Fused Ring Systems as Novel P2 Ligands: Structure-Activity Studies, Biological and X-ray Structural Analysis.
J. Med. Chem., 61:4561-4577, 2018

PubMed Abstract: The design, synthesis, and biological evaluation of a new class of HIV-1 protease inhibitors containing stereochemically defined fused tricyclic polyethers as the P2 ligands and a variety of sulfonamide derivatives as the P2' ligands are described. A number of ring sizes and various substituent effects were investigated to enhance the ligand-backbone interactions in the protease active site. Inhibitors 5c and 5d containing this unprecedented fused 6-5-5 ring system as the P2 ligand, an aminobenzothiazole as the P2' ligand, and a difluorophenylmethyl as the P1 ligand exhibited exceptional enzyme inhibitory potency and maintained excellent antiviral activity against a panel of highly multidrug-resistant HIV-1 variants. The umbrella-like P2 ligand for these inhibitors has been synthesized efficiently in an optically active form using a Pauson-Khand cyclization reaction as the key step. The racemic alcohols were resolved efficiently using a lipase catalyzed enzymatic resolution. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

PubMed: 29763303
DOI: 10.1021/acs.jmedchem.8b00298

Experimental method

X-RAY DIFFRACTION (1.13 Å)