OncoWitan, Lille (Wasquehal), 59290, France.
University of Lille, Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France.
Comput Biol Chem. 2020 Dec;89:107409. doi: 10.1016/j.compbiolchem.2020.107409. Epub 2020 Oct 31.
The fumigaclavines represent a small group of clavine-type alkaloids produced by the pathogenic fungus Aspergillus fumigatus. The leading compound in the family is fumigaclavine C (Fm-C) endowed with potent anti-inflammatory properties. Fm-C represses the production of several inflammatory cytokines in cells via a mechanism implicating a reduced nucleo-cytoplasmic transport and extracellular export of the alarmin protein HMGB1, through a direct drug-protein interaction, and a down-regulation of HMGB1 expression. We have investigated the interaction of Fm-C with HMGB1 using two complementary forms of the HMG-box protein, in its free and DNA-bound configurations, using molecular modeling. We identified up to six potential binding sites for Fm-C in the vicinity of the B-box of HMGB1, with the site designated Lys-103 being the most favored and maintained when the protein is bound to a 16-base pair DNA oligonucleotide. Structure-binding relationships have been explored through the comparison of the HMGB1-binding properties of fumigaclavines A, B and C, and the related alkaloid lysergic acid diethylamide (LSD). Both the C-9 acetyl group and C-2 dimethylallyl side chain of Fm-C contribute importantly to the protein interaction. LSD appears also to form stable complexes with free HMGB1. According to the calculated empirical energies of interaction (ΔE), the compounds rank in the order: Fm-C ∼ LSD < Fm-A < Fm-B, for binding to HMGB1. The study helps to better comprehend the mechanism of action of Fm-C, and its anti-inflammatory and anticancer properties.
烟曲霉素类化合物是由致病真菌烟曲霉产生的一组小型裂环烯醚萜类生物碱。该家族的主要化合物是具有强大抗炎特性的烟曲霉素 C（Fm-C）。Fm-C 通过一种机制抑制细胞中几种炎症细胞因子的产生，该机制涉及 HMGB1 预警蛋白的核质转运和细胞外输出减少，通过直接药物-蛋白相互作用，以及下调 HMGB1 的表达。我们使用两种形式的 HMG 盒蛋白（其游离形式和与 DNA 结合的形式），通过分子建模研究了 Fm-C 与 HMGB1 的相互作用。我们在 HMGB1 的 B 盒附近确定了多达六个潜在的 Fm-C 结合位点，其中指定为 Lys-103 的位点是最有利的，并在蛋白质与 16 个碱基对 DNA 寡核苷酸结合时保持不变。通过比较烟曲霉素 A、B 和 C 以及相关生物碱麦角酸二乙酰胺（LSD）对 HMGB1 的结合特性，探索了结构-结合关系。Fm-C 的 C-9 乙酰基和 C-2 二甲基丙烯基侧链对蛋白相互作用都很重要。LSD 似乎也与游离的 HMGB1 形成稳定的复合物。根据计算的相互作用经验能量（ΔE），化合物的排列顺序为：Fm-C∼LSD<Fm-A<Fm-B，用于与 HMGB1 结合。该研究有助于更好地理解 Fm-C 的作用机制及其抗炎和抗癌特性。
