双膦酸化合物对基质金属蛋白酶的抑制效应及机理  

Activity Assay and Mechanism Study of Bisphosphonates as Matrix Metalloproteinase Inhibitors

作　　者：刘星辰[1] 李洪伟[1] 王烨[2] 蒋坤[2] 房学迅[2] 吴玉清[1] 

机构地区：[1]吉林大学超分子结构与材料国家重点实验室,长春130012 [2]吉林大学分子酶学工程教育部重点实验室,长春130021

出　　处：《高等学校化学学报》2010年第1期88-93,共6页Chemical Journal of Chinese Universities

基　　金：国家自然科学基金(批准号:20973073;20773051);国家"九七三"计划项目(批准号:2007CB808006);吉林省科技发展计划项目(批准号:20070926-01);教育部新世纪优秀人才支持计划资助

摘　　要：根据基质金属蛋白酶(MMPs)的活性位点附近三维空间结构,设计合成了4种双膦酸类化合物,利用酶促反应动力学方法对比测试了双膦酸化合物及阿伦磷酸钠(Alendronate)对MMPs的抑制效果;结合分子对接方法以及荧光滴定光谱研究了双膦酸化合物与MMPs的分子识别和作用机理,并得到了二者的结合模型.Matrix metalloproteinases（ MMPs）, a group of zinc-dependent metalloproteinases, are responsible for the hydrolytic breakdown of extracellular matrix. Aberrantly over expression of MMPs has been associated with much human pathology including cancer, arthritis, and heart disease etc. Therefore, the development of MMPs inhibitors to drugs has always been of great interest to scientific institutions. Bisphosphonates were reported to be a new kind of MMPs inhibitors with great potential. According to the 3-dimensional structure, 4 bisphosphonates are designed, synthesized and tested against several typical MMPs. The inhibitory activities toward MMP-2, MMP-3 and MMP-9 were tested in vitro using flourometrie method. The results show micromolar-level activity and modest selectivity toward MMPs. Molecular docking study and fluorometic titration spectra were performed to reveal the recognition and inhibition mechanism between MMPs and bisphosphonates, and the binding mode between them was proposed.

关 键 词：基质金属蛋白酶 抑制剂 双膦酸 分子识别 机理 

分 类 号：O641[理学—物理化学]