基于酶结构的新型基质金属蛋白酶抑制剂设计、合成与活性评价

Design, synthesis and activity evaluation of novel matrix metalloproteinases inhibitors based on the structure of enzyme

摘要: 设计并合成了一系列新结构类型的基质金属蛋白酶抑制剂；借助FlexX对接软件，利用丙二酸和丁二酸的电性和结构特征使抑制剂分子与Zn²⁺形成双齿甚至三齿配位作用，并引入长的疏水性片段结合于蛋白酶的S₁′腔穴；该类化合物大多对MMP-2表现出微摩尔级的选择性抑制作用，并发现一个具有较好活性的化合物；进一步结构修饰和优化有望寻找到活性更高、生物利用度更好的MMP-2抑制剂先导化合物。

Abstract: A novel inhibitor series for matrix metalloproteinases (MMPs) were designed and synthesized. Using succinate and malonate as zinc binding groups and long hydrophobic substituents to bind with S₁′ pockets, the compounds showed micromolar inhibition and selectivity for MMP-2 over others. And we found a better activity compound. It is a chance to find a better precursor of MMP-2 inhibitors with activity and bioavailability by further optimization of compounds.