基于结构的 D-巯甲丙脯酸优化用于发现有效的 NDM-1 抑制剂。
Structure-guided optimization of D-captopril for discovery of potent NDM-1 inhibitors.
机构信息
Department of Biology, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research and Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen 518055, Guangdong, China.
Beijing National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Department of Chemical Biology, College of Chemistry and Molecular Engineering, Synthetic and Functional Biomolecules Center and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
出版信息
Bioorg Med Chem. 2021 Jan 1;29:115902. doi: 10.1016/j.bmc.2020.115902. Epub 2020 Dec 3.
β-lactam antibiotics have long been the mainstay for the treatment of bacterial infections. New Delhi metallo-β-lactamase 1 (NDM-1) is able to hydrolyze nearly all β-lactam antibiotics and even clinically used serine-β-lactamase inhibitors. The wide and rapid spreading of NDM-1 gene among pathogenic bacteria has attracted extensive attention, therefore high potency NDM-1 inhibitors are urgently needed. Here we report a series of structure-guided design of D-captopril derivatives that can inhibit the activity of NDM-1 in vitro and at cellular levels. Structural comparison indicates the mechanisms of inhibition enhancement and provides insights for further inhibitor optimization.
β-内酰胺类抗生素一直是治疗细菌感染的主要药物。新德里金属β-内酰胺酶 1（NDM-1）能够水解几乎所有的β-内酰胺类抗生素，甚至包括临床上使用的丝氨酸β-内酰胺酶抑制剂。NDM-1 基因在致病菌中的广泛快速传播引起了广泛关注，因此迫切需要高效的 NDM-1 抑制剂。在这里，我们报告了一系列基于结构的 D-巯基脯氨酸衍生物的设计，这些衍生物可以在体外和细胞水平上抑制 NDM-1 的活性。结构比较表明了抑制增强的机制，并为进一步的抑制剂优化提供了思路。
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