腈基类化合物对半胱氨酸蛋白酶的抑制机理

The Mechanism of Inhibition of Cysteine Protease

半胱氨酸蛋白酶是人体自身产生的重要酶类物质,它广泛的参与人体新陈代谢和蛋白的水解。但过量产生的半胱氨酸蛋白酶会导致骨质疏松和乳腺癌。腈基类化合物分子是一种新发现的具有抑制半胱氨酸蛋白酶作用的靶向药物分子,高效且低副作用。但是它的抑制机理一直没有得到解决。本文介绍借助量子力学/分子力学(QM/MM)的计算研究,解得了此类化合物对于半胱氨酸蛋白酶的抑制机理,并借助分子学软件设计了一种新型药物分子,有助进一步药物研究。

Cysteine protease is a vital enzyme for human metabolism and involved in a proteolysis reaction in human body. However, over-expressed cysteine proteases can cause serious diseases such as osteoporosis and breast cancer. Nitrile-based inhibitors are newly-discovered substrates as well as drugs which can inhibit cysteine proteases with high efficiency and low side-effects. However, the mechanism of inhibition remains unknown. This paper illustrates a novel computational calculation performed by quantum mechanics/molecular mechanics （QM/MM） to resolve this mechanism. We find a stepwise mechanism whereby the deprotonated anionic sulfur atom from cysteine of the active site of Cathepsin K attacks a nitrile containing substrate to form an intermediate structure, followed by a deprotonation reaction to form a lower energy product state structure, and therefore, this mechanism of inhibition of cysteine protease has been resolved.