5ULT

HIV-1 wild Type protease with GRL-100-13A (a Crown-like Oxotricyclic Core as the P2-Ligand with the sulfonamide isostere as the P2' group)

Summary for 5ULT

• Entry DOI: 10.2210/pdb5ult/pdb
• Related: 2IEN 5TYR 5UOV 5UPZ
• Descriptor: Protease, SODIUM ION, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: crown-like oxotricyclic core, hiv-1 protease inhibitor grl-100-13a, darunavir, multidrug-resistant, hydrolase inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 2
• Total formula weight: 22163.96

Authors

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (deposition date: 2017-01-25, release date: 2017-05-03, Last modification date: 2023-10-04)

Primary citation

Ghosh, A.K.,Rao, K.V.,Nyalapatla, P.R.,Osswald, H.L.,Martyr, C.D.,Aoki, M.,Hayashi, H.,Agniswamy, J.,Wang, Y.F.,Bulut, H.,Das, D.,Weber, I.T.,Mitsuya, H.
Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.
J. Med. Chem., 60:4267-4278, 2017

PubMed Abstract: Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. 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: 28418652
DOI: 10.1021/acs.jmedchem.7b00172

Experimental method

X-RAY DIFFRACTION (1.53 Å)