7D83

Crystal structure of HIV-1 integrase catalytic core domain in complex with 2-(tert-butoxy)-2-(2-(3-cyclohexylureido)-3,6-dimethyl-5-(5-methylchroman-6-yl)pyridin-4-yl)acetic acid

Summary for 7D83

• Entry DOI: 10.2210/pdb7d83/pdb
• Descriptor: Integrase, SULFATE ION, (2S)-2-[2-(cyclohexylcarbamoylamino)-3,6-dimethyl-5-(5-methyl-3,4-dihydro-2H-chromen-6-yl)pyridin-4-yl]-2-[(2-methylpropan-2-yl)oxy]ethanoic acid, ... (4 entities in total)
• Functional Keywords: hiv-1 integrase, viral protein
• Biological source: Human immunodeficiency virus type 1 group M subtype B (isolate NY5) (HIV-1)
• Total number of polymer chains: 1
• Total formula weight: 19246.58

Authors

Sugiyama, S.,Sekiguchi, Y. (deposition date: 2020-10-07, release date: 2021-01-13, Last modification date: 2024-10-23)

Primary citation

Sugiyama, S.,Akiyama, T.,Taoda, Y.,Iwaki, T.,Matsuoka, E.,Akihisa, E.,Seki, T.,Yoshinaga, T.,Kawasuji, T.
Discovery of novel HIV-1 integrase-LEDGF/p75 allosteric inhibitors based on a pyridine scaffold forming an intramolecular hydrogen bond.
Bioorg.Med.Chem.Lett., 33:127742-127742, 2020

PubMed Abstract: We have discovered HIV-1 novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a pyridine scaffold forming an intramolecular hydrogen bond. Scaffolds containing a pyridine moiety have been studied extensively and we have already reported that substituents extending from the C1 position contributed to the antiviral potency. In this study, we designed a new pyridine scaffold 2 with a substituent at the C1 position. Interestingly, during attempts at optimization, we found that the direction of the C1 substituents with an intramolecular hydrogen bond contributed to the antiviral potency. Compound 34f exhibited better antiviral potency against WT and the T174I mutant (EC (WT) = 6.6 nM, EC (T174I) = 270 nM) than BI 224436 (EC (WT) = 22 nM, EC (T174I) > 5000 nM).

PubMed: 33316407
DOI: 10.1016/j.bmcl.2020.127742

Experimental method

X-RAY DIFFRACTION (2.43 Å)