9OBI

Room Temperature X-Ray Structure of HIV-1 Protease in Complex with Inhibitor GRL-075-24A

This is a non-PDB format compatible entry.

Summary for 9OBI

• Entry DOI: 10.2210/pdb9obi/pdb
• Descriptor: Protease, (1S,5S,7S)-7-(2-methoxyphenyl)-8-oxaspiro[4.5]decan-1-yl {(2S,3R)-3-hydroxy-4-[(4-methoxybenzene-1-sulfonyl)(2-methylpropyl)amino]-1-phenylbutan-2-yl}carbamate, CHLORIDE ION, ... (4 entities in total)
• Functional Keywords: aspartic protease, enzyme-inhibitor complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 8
• Total formula weight: 88775.83

Authors

Bhandari, D.,Kovalevsky, A.,Ghosh, A.K. (deposition date: 2025-04-22, release date: 2025-07-23)

Primary citation

Ghosh, A.K.,Shaktah, R.,Ghosh, A.K.,Johnson, M.E.,Bhandari, D.,Amano, M.,Aoki, M.,Kovalevsky, A.,Mitsuya, H.
Design, synthesis, evaluation and X-ray structural studies of potent HIV-1 protease inhibitors containing substituted oxaspirocyclic carbamates as the P2 ligands.
Eur.J.Med.Chem., 297:117880-117880, 2025

PubMed Abstract: We report here the design, synthesis and evaluation of a series of HIV-1 protease inhibitors that incorporate substituted oxaspirocyclic carbamate derivatives to serve as the P2 ligands. Various substituted ligand derivatives were synthesized in a racemic manner, using a tandem Prins/pinacol reaction as the key reaction. This reaction sets the relative stereochemistry of the oxaspirocyclic template in a highly diastereoselective manner. Reaction of the resulting ketone with enantiopure (S)-tert-butyl sulfinamide provided a convenient pathway to resolve the oxaspirocyclic ketone derivatives. The absolute stereochemical identity was determined by X-ray crystallography. The structure-activity studies demonstrate the effect of the stereochemistry of the oxaspirocyclic ring systems as well as the substitution effect on the aromatic ring. Several inhibitors exhibited potent HIV-1 protease inhibitory activity. One of these inhibitors displayed subnanomolar HIV-1 protease affinity and also exhibited potent antiviral activity. A high-resolution X-ray crystal structure of this inhibitor-bound HIV-1 protease show that the oxaspirocyclic P2 ligand forms an unconventional C-H⋯O bond with the backbone carboxyl group of Gly48' and an interesting N-H … π interaction with the aromatic ring in the S2 subsite of HIV-1 protease active site.

PubMed: 40644923
DOI: 10.1016/j.ejmech.2025.117880

Experimental method

X-RAY DIFFRACTION (1.7 Å)