Yu Zhu-Jun, Liu Sha, Zhou Shu, Li Hui, Yang Fan, Yang Ling-Ling, Wu Yong, Guo Li, Li Guo-Bo
Key Laboratory of Drug Targeting and Drug Delivery System of Ministry of Education, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
College of Food and Bioengineering, Xihua University, Sichuan 610039, China.
Bioorg Med Chem Lett. 2018 Apr 1;28(6):1037-1042. doi: 10.1016/j.bmcl.2018.02.025. Epub 2018 Feb 14.
Rosmarinic acid (RA), a polyphenolic phytochemical, has broad-spectrum biological and pharmacological activity. A virtual target screening method termed IFPTarget combined with enzyme inhibition assays led to the identification of the clinically relevant metallo-β-lactamase (MBL) VIM-2 as one of unexploited targets of RA. The enzyme kinetic studies indicated that RA is a fully reversible, substrate-competitive VIM-2 inhibitor. The isothermal titration calorimetry (ITC) analyses revealed that the initial binding of RA to VIM-2 is mainly due to enthalpy contribution. Further inhibition assays with RA related compounds revealed that salvianolic acid A, a derivative of RA, manifests potent inhibition to VIM-2, more interestingly, which shows inhibitory activity against the NDM-1, another clinically relevant MBL subtype, and the serine-β-lactamase TEM-1 that is structurally and mechanistically distinct from the VIM-2 and NDM-1.
迷迭香酸（RA）是一种多酚类植物化学物质，具有广谱的生物学和药理活性。一种名为IFPTarget的虚拟靶点筛选方法结合酶抑制试验，确定了临床相关的金属β-内酰胺酶（MBL）VIM-2是RA尚未开发的靶点之一。酶动力学研究表明，RA是一种完全可逆的、底物竞争性的VIM-2抑制剂。等温滴定量热法（ITC）分析表明，RA与VIM-2的初始结合主要是由于焓的贡献。对RA相关化合物的进一步抑制试验表明，RA的衍生物丹酚酸A对VIM-2表现出强效抑制作用，更有趣的是，它对另一种临床相关的MBL亚型NDM-1以及在结构和机制上与VIM-2和NDM-1不同的丝氨酸β-内酰胺酶TEM-1也具有抑制活性。
