7T9O

HIV Integrase in complex with Compound-25

7T9O の概要

• エントリーDOI: 10.2210/pdb7t9o/pdb
• 分子名称: Integrase, SULFATE ION, (2S)-tert-butoxy[4-(4,4-dimethylpiperidin-1-yl)-5-{4-[2-(4-fluorophenyl)ethoxy]phenyl}-2,6-dimethylpyridin-3-yl]acetic acid, ... (5 entities in total)
• 機能のキーワード: dna integration, aids, rnaseh, ledgf, endonuclease, hiv-1 integrase, dna binding protein, viral protein
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20628.27

構造登録者

Khan, J.A.,Lewis, H.,Kish, K. (登録日: 2021-12-19, 公開日: 2022-04-06, 最終更新日: 2023-10-18)

主引用文献

Naidu, B.N.,Patel, M.,McAuliffe, B.,Ding, B.,Cianci, C.,Simmermacher, J.,Jenkins, S.,Parker, D.D.,Sivaprakasam, P.,Khan, J.A.,Kish, K.,Lewis, H.,Hanumegowda, U.,Krystal, M.,Meanwell, N.A.,Kadow, J.F.
Design, Synthesis, and Preclinical Profiling of GSK3739936 (BMS-986180), an Allosteric Inhibitor of HIV-1 Integrase with Broad-Spectrum Activity toward 124/125 Polymorphs.
J.Med.Chem., 65:4949-4971, 2022

PubMed Abstract: Allosteric HIV-1 integrase inhibitors (ALLINIs) have garnered special interest because of their novel mechanism of action: they inhibit HIV-1 replication by promoting aberrant integrase multimerization, leading to the production of replication-deficient viral particles. The binding site of ALLINIs is in a well-defined pocket formed at the interface of two integrase monomers that is characterized by conserved residues along with two polymorphic amino acids at residues 124 and 125. The design, synthesis, and optimization of pyridine-based allosteric integrase inhibitors are reported here. Optimization was conducted with a specific emphasis on the inhibition of the 124/125 polymorphs such that the designed compounds showed excellent potency against majority of the 124/125 variants. profiling of promising preclinical lead showed that it exhibited a good pharmacokinetic (PK) profile in preclinical species, which resulted in a low predicted human efficacious dose. However, findings in rat toxicology studies precluded further development of .

PubMed: 35235334
DOI: 10.1021/acs.jmedchem.1c02169

実験手法

X-RAY DIFFRACTION (1.95 Å)