6B4N

a hydroxymethyl functionality at the 4-position of the 2-phenyloxazole moiety of HIV-1 protease inhibitors involving the P2' ligands

6B4N の概要

• エントリーDOI: 10.2210/pdb6b4n/pdb
• 関連するPDBエントリー: 2IEN
• 分子名称: Protease, methyl 2-{4-[{(2R,3S)-3-[({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy}carbonyl)amino]-2-hydroxy-4-phenylbutyl}(2-methylpropyl)sulfamoyl]phenyl}-1,3-oxazole-4-carboxylate, SODIUM ION, ... (5 entities in total)
• 機能のキーワード: hiv protease, the 2-phenyloxazole moiety inhibitor, p2' ligands, drug resistance, hydrolase, antiviral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Human immunodeficiency virus 1
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 22326.88

構造登録者

Wang, Y.-F.,Agniswamy, J.,Weber, I.T. (登録日: 2017-09-27, 公開日: 2017-11-22, 最終更新日: 2023-10-04)

主引用文献

Ghosh, A.K.,Fyvie, W.S.,Brindisi, M.,Steffey, M.,Agniswamy, J.,Wang, Y.F.,Aoki, M.,Amano, M.,Weber, I.T.,Mitsuya, H.
Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir.
ChemMedChem, 12:1942-1952, 2017

PubMed Abstract: The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic HIV-1 protease inhibitors with rationally designed P2' ligands are described. The inhibitors are designed to enhance backbone binding interactions, particularly at the S2' subsite. Synthesis of inhibitors was carried out efficiently. The stereochemistry of alcohol functionalities of the P2' ligands was set by asymmetric reduction of the corresponding ketone using (R,R)- or (S,S)-Noyori catalysts. A number of inhibitors displayed very potent enzyme inhibitory and antiviral activity. Inhibitors 3g and 3h showed enzyme K values of 27.9 and 49.7 pm and antiviral activity of 6.2 and 3.9 nm, respectively. These inhibitors also remained quite potent against darunavir-resistant HIV-1 variants. An X-ray structure of inhibitor 3g in complex with HIV-1 protease revealed key interactions in the S2' subsite.

PubMed: 29110408
DOI: 10.1002/cmdc.201700614

実験手法

X-RAY DIFFRACTION (1.3 Å)