Clemens-Schöpf Institute of Organic Chemistry and Biochemistry, Technische Universität Darmstadt, Petersenstr. 22, 64287 Darmstadt, Germany.
Org Biomol Chem. 2012 Oct 14;10(38):7753-62. doi: 10.1039/c2ob26162f.
A comparative study on in vitro and in silico inhibition of trypsin and matriptase by derivatives of the sunflower trypsin inhibitor-1 at near physiological pH is reported. Besides wild-type bicyclic SFTI-1, monocyclic variants possessing native cystine as well as redox-stable triazolyl side-chain macrocyclization motifs were studied for the first time in matriptase inhibition assays. Interestingly, monocyclic SFTI-1[1,14] demonstrated higher potency against this pharmacologically relevant protease compared to its bicyclic counterpart. Structural analysis of binding/inhibition of investigated SFTI-1 derivatives was performed using a combination of molecular dynamics simulations and docking experiments. In silico data were in good accordance with in vitro results, indicating the importance of the terminal inhibitor regions for the affinity towards matriptase. Presented work gives new perspectives for the optimization of the SFTI-1 framework towards in vivo applications.
报道了在近生理 pH 值条件下，通过向日葵胰蛋白酶抑制剂-1 的衍生物对胰蛋白酶和组织蛋白酶抑制的体外和计算比较研究。除了野生型双环 SFTI-1 外，首次在组织蛋白酶抑制试验中研究了具有天然半胱氨酸的单环变体以及氧化还原稳定的三唑基侧链大环化基序。有趣的是，与双环类似物相比，单环 SFTI-1[1,14]对这种药理相关蛋白酶表现出更高的效力。使用分子动力学模拟和对接实验的组合对所研究的 SFTI-1 衍生物的结合/抑制进行了结构分析。计算数据与体外结果非常吻合，表明末端抑制剂区域对与组织蛋白酶亲和力的重要性。目前的工作为优化 SFTI-1 框架以应用于体内提供了新的视角。
