8ESX

HIV protease in complex with benzoxaborolone analog of darunavir

8ESX の概要

• エントリーDOI: 10.2210/pdb8esx/pdb
• 分子名称: Protease, GLYCEROL, CHLORIDE ION, ... (7 entities in total)
• 機能のキーワード: virus, protease, inhibitor, boron, hydrolase, hydrolase-inhibitor complex, 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: 22381.31

構造登録者

Windsor, I.W.,Graham, B.J.,Raines, R.T. (登録日: 2022-10-15, 公開日: 2023-02-08, 最終更新日: 2023-10-25)

主引用文献

Graham, B.J.,Windsor, I.W.,Raines, R.T.
Inhibition of HIV-1 Protease by a Boronic Acid with High Oxidative Stability.
Acs Med.Chem.Lett., 14:171-175, 2023

PubMed Abstract: HIV-1 protease is an important target for pharmaceutical intervention in HIV infection. Extensive structure-based drug design led to darunavir becoming a key chemotherapeutic agent. We replaced the aniline group of darunavir with a benzoxaborolone to form BOL-darunavir. This analogue has the same potency as darunavir as an inhibitor of catalysis by wild-type HIV-1 protease and, unlike darunavir, does not lose potency as an inhibitor of the common D30N variant. Moreover, BOL-darunavir is much more stable to oxidation than is a simple phenylboronic acid analogue of darunavir. X-ray crystallography revealed an extensive network of hydrogen bonds between the enzyme and benzoxaborolone moiety, including a novel direct hydrogen bond from a main-chain nitrogen to the carbonyl oxygen of the benzoxaborolone moiety that displaces a water molecule. These data highlight the utility of benzoxaborolone as a pharmacophore.

PubMed: 36793428
DOI: 10.1021/acsmedchemlett.2c00464

実験手法

X-RAY DIFFRACTION (1.35 Å)