6C8Y

D30N HIV-1 protease in complex with a phenylboronic acid (P2') analog of darunavir

6C8Y の概要

• エントリーDOI: 10.2210/pdb6c8y/pdb
• 分子名称: Protease, CHLORIDE ION, [4-[[(2~{R},3~{S})-3-[[(3~{a}~{S},4~{R},6~{a}~{R})-2,3,3~{a},4,5,6~{a}-hexahydrofuro[2,3-b]furan-4-yl]oxycarbonylamino]-2-oxidanyl-4-phenyl-butyl]-(2-methylpropyl)sulfamoyl]phenyl]-oxidanyl-oxidanylidene-boron, ... (5 entities in total)
• 機能のキーワード: hiv, protease, boronic acid, inhibitor, 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: 22253.29

構造登録者

Windsor, I.W.,Raines, R.T.,Forest, K.T. (登録日: 2018-01-25, 公開日: 2018-12-05, 最終更新日: 2023-10-04)

主引用文献

Windsor, I.W.,Palte, M.J.,Lukesh 3rd., J.C.,Gold, B.,Forest, K.T.,Raines, R.T.
Sub-picomolar Inhibition of HIV-1 Protease with a Boronic Acid.
J. Am. Chem. Soc., 140:14015-14018, 2018

PubMed Abstract: Boronic acids have been typecast as moieties for covalent complexation and are employed only rarely as agents for non-covalent recognition. By exploiting the profuse ability of a boronic acid group to form hydrogen bonds, we have developed an inhibitor of HIV-1 protease with extraordinary affinity. Specifically, we find that replacing an aniline moiety in darunavir with a phenylboronic acid leads to 20-fold greater affinity for the protease. X-ray crystallography demonstrates that the boronic acid group participates in three hydrogen bonds, more than the amino group of darunavir or any other analog. Importantly, the boronic acid maintains its hydrogen bonds and its affinity for the drug-resistant D30N variant of HIV-1 protease. The BOH···OC hydrogen bonds between the boronic acid hydroxy group and Asp30 (or Asn30) of the protease are short ( r = 2.2 Å), and density functional theory analysis reveals a high degree of covalency. These data highlight the utility of boronic acids as versatile functional groups in the design of small-molecule ligands.

PubMed: 30346745
DOI: 10.1021/jacs.8b07366

実験手法

X-RAY DIFFRACTION (1.942 Å)