7WCE

Crystal structure of HIV-1 integrase catalytic core domain in complex with (2S)-2-(tert-Butoxy)-2-(10-fluoro-2-(2-hydroxy-4-methylphenyl)-1,4-dimethyl-5-(methylsulfonyl)-5,6-dihydrophenanthridin-3-yl)acetic acid

Summary for 7WCE

• Entry DOI: 10.2210/pdb7wce/pdb
• Descriptor: Integrase catalytic, SULFATE ION, (2S)-2-[10-fluoranyl-1,4-dimethyl-2-(4-methyl-2-oxidanyl-phenyl)-5-methylsulfonyl-6H-phenanthridin-3-yl]-2-[(2-methylpropan-2-yl)oxy]ethanoic acid, ... (5 entities in total)
• Functional Keywords: hiv-1 integrase, viral protein, hydrolase
• Biological source: Human immunodeficiency virus type 1 (NEW YORK-5 ISOLATE)
• Total number of polymer chains: 1
• Total formula weight: 19260.57

Authors

Taoda, Y.,Sekiguchi, Y. (deposition date: 2021-12-20, release date: 2022-09-07, Last modification date: 2024-10-30)

Primary citation

Taoda, Y.,Akiyama, T.,Tomita, K.,Fujiwara-Kitamura, M.,Tamura, Y.,Kawasuji, T.,Matsuoka, E.,Akihisa, E.,Seki, T.,Yoshinaga, T.
Discovery of tricyclic HIV-1 integrase-LEDGF/p75 allosteric inhibitors by intramolecular direct arylation reaction.
Bioorg.Med.Chem.Lett., 64:128664-128664, 2022

PubMed Abstract: We have been conducting exploratory research to develop human immunodeficiency virus type-1 (HIV-1) integrase-LEDGF/p75 allosteric inhibitors (INLAIs). Here, we report on a newly designed compound with a tricyclic scaffold that shows promise as an inhibitor. Various scaffolds were synthesized by intramolecular direct arylation reaction to fix the position of a lipophilic side chain required for antiviral activity. Among these, the compound having an N-mesyl dihydrophenanthridine ring showed the best antiviral activity. Compound 42i, prepared by side chain optimization of the C-4 and C-6 positions, exhibited high antiviral activity against wild-type (WT) and the T174I mutant (EC (WT) = 4.6 nM, EC (T174I) = 83 nM) with a good PK profile. Based on co-crystal structural analysis of compound 42i and WT HIV-1 IN CCD, we discuss the interaction important for high antiviral activity.

PubMed: 35272008
DOI: 10.1016/j.bmcl.2022.128664

Experimental method

X-RAY DIFFRACTION (1.85 Å)