Identification of lignans as ATP citrate lyase (ACLY) inhibitors from the roots of Pouzolzia zeylanica

AbstractAbstractA new lignan, named pouzolignan P (1), together with 14 known ones (2 − 15) were isolated from the roots of Pouzolzia zeylanica (L.) Benn. Their structures were deduced based on the detailed spectroscopic analysis. All the isolates were evaluated for their inhibitory activities toward the ATP citrate lyase (ACLY). Among them, four lignans, isopouzolignan K (3), gnemontanins E (5), gnetuhainin I (6), and styraxlignolide D (15) showed excellent ACLY inhibitory effect with IC50 values of 9.06, 0.59, 2.63, and 7.62 μM, respectively. These compounds were further evaluated for their cholesterol-lowing effects on ox-LDL-induced high-cholesterol HepG2 cells. Compound 15 emerges as the most potent ACLY inhibitor, which significantly decreased the TC level in a dose-dependent manner. In addition, molecular docking simulations elucidated that 15 formed a strong hydrogen-bond interaction with Glu599 of ACLY, which was an important site responsible for the enzyme catalytic activity.Graphical AbstractKeywords: Pouzolzia zeylanicalignansATP citrate lyase (ACLY) inhibitors Disclosure statementNo potential conflict of interest was reported by the authors.Additional informationFundingThis work was supported by the [Hong Kong Scholars program] under Grant [XJ2019054], [Nantong Health Commission Project] under Grant [MSZ2022022], and partial supported by [Administration of Traditional Chinese Medicine of Jiangsu Province] under Grand [YB201960].