8ZHA

HIV-1 integrase core domain in complex with compound 15

This is a non-PDB format compatible entry.

Summary for 8ZHA

• Entry DOI: 10.2210/pdb8zha/pdb
• Related: 8ZH4
• Descriptor: Integrase, TETRAETHYLENE GLYCOL, (2~{S})-2-[7-(cycloheptylcarbamoyl)-4',5-dimethyl-spiro[1,2-dihydroindene-3,1'-cyclohexane]-4-yl]-2-[(2-methylpropan-2-yl)oxy]ethanoic acid, ... (5 entities in total)
• Functional Keywords: hiv, integrase, inhibitor, viral protein
• Biological source: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
• Total number of polymer chains: 1
• Total formula weight: 19433.71

Authors

Furuzono, T.,Orita, T.,Nomura, A.,Adachi, T. (deposition date: 2024-05-10, release date: 2024-07-10, Last modification date: 2024-10-23)

Primary citation

Adachi, K.,Manabe, T.,Yamasaki, T.,Suma, A.,Orita, T.,Furuzono, T.,Adachi, T.,Ohata, Y.,Akiyama, Y.,Miyazaki, S.
Design and synthesis of novel and potent allosteric HIV-1 integrase inhibitors with a spirocyclic moiety.
Bioorg.Med.Chem.Lett., 110:129864-129864, 2024

PubMed Abstract: We report herein the design and discovery of novel allosteric HIV-1 integrase inhibitors. Our design concept utilized the spirocyclic moiety to restrain the flexibility of the conformation of the lipophilic part of the inhibitor. Compound 5 showed antiviral activity by binding to the nuclear lens epithelium-derived growth factor (LEDGF/p75) binding site of HIV-1 integrase (IN). The introduction of a lipophilic amide substituent into the central benzene ring resulted in a significant increase in antiviral activity against HIV-1 WT X-ray crystallography of compound 15 in complex with the integrase revealed the presence of a hydrogen bond between the oxygen atom of the amide of compound 15 and the hydroxyl group of the T125 side chain. Chiral compound 17 showed high antiviral activity, good bioavailability, and low clearance in rats.

PubMed: 38942126
DOI: 10.1016/j.bmcl.2024.129864

Experimental method

X-RAY DIFFRACTION (1.95 Å)