Vitale Rosa Maria, Antenucci Lina, Gavagnin Margherita, Raimo Gennaro, Amodeo Pietro
a Institute of Biomolecular Chemistry (ICB) , National Council Research (CNR) of Italy , Pozzuoli , Italy.
b Department of Medicine and Health Sciences , University of Molise , Campobasso , Italy.
J Enzyme Inhib Med Chem. 2017 Dec;32(1):345-354. doi: 10.1080/14756366.2016.1252758.
Fraxamoside, a macrocyclic secoiridoid glucoside featuring a hydroxytyrosol group, was recently identified as a xanthine oxidase inhibitor (XOI) comparable in potency in vitro to the standard antigout drug allopurinol. However, this activity and its considerably higher value than its derivatives oleuropein, oleoside 11-methyl ester, and hydroxytyrosol are not explained by structure-activity relationships (SARs) of known XOIs. To exclude allosteric mechanisms, we first determined the inhibition kinetic of fraxamoside. The resulting competitive mechanism prompted a computational SAR characterization, combining molecular docking and dynamics, which fully explained the behavior of fraxamoside and its derivatives, attributed the higher activity of the former to conformational properties of its macrocycle, and showed a substantial contribution of the glycosidic moiety to binding, in striking contrast with glycoside derivatives of most other XOIs. Overall, fraxamoside emerged as a lead compound for a new class of XOIs potentially characterized by reduced interference with purine metabolism.
紫铆因，一种具有羟基酪醇基团的大环裂环环烯醚萜苷，最近被鉴定为一种黄嘌呤氧化酶抑制剂（XOI），其体外活性与标准抗痛风药物别嘌醇相当。然而，这种活性及其比其衍生物橄榄苦苷、橄榄苷11 - 甲酯和羟基酪醇高得多的活性，无法用已知XOI的构效关系（SAR）来解释。为了排除变构机制，我们首先确定了紫铆因的抑制动力学。由此产生的竞争机制促使我们结合分子对接和动力学进行计算SAR表征，这充分解释了紫铆因及其衍生物的行为，将前者的较高活性归因于其大环的构象性质，并表明糖苷部分对结合有重大贡献，这与大多数其他XOI的糖苷衍生物形成鲜明对比。总体而言，紫铆因成为一类新型XOI的先导化合物，这类XOI的潜在特征可能是对嘌呤代谢的干扰减少。
