Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, México 04510, DF, Mexico.
J Mol Graph Model. 2012 May;35:28-35. doi: 10.1016/j.jmgm.2012.01.003. Epub 2012 Jan 20.
Cysteine proteases from parasites as well as from mammals are promising drug targets for parasitic infections and systemic human diseases, respectively. Many reversible and irreversible inhibitors of this very large class of proteins have been designed. Among others, molecules with a nitrile moiety, which is a group that is susceptible to a nucleophilic attack by the enzyme, have been identified as good inhibitors. Although it is known that the nitrile group binds covalently to Cys25, there are no reports about the energetics involved in the mechanism of this process. Herein, density functional theory and quantum semi-empirical calculations were conducted in order to study the molecular recognition of cysteine proteases by nitrile-containing molecules. Results reported in this paper suggest an interaction that starts with a nucleophilic attack from the Cys25 to the inhibitor followed by a proton transfer from His162. Only one transition state was detected; however, we found the existence of an energy plateau in the potential energy surface. Based on the proposed mechanism, some structural features that could improve the biological activity of nitrile-containing molecules toward cysteine proteases are discussed.
寄生虫和哺乳动物的半胱氨酸蛋白酶分别是寄生虫感染和系统性人类疾病的有前途的药物靶点。已经设计了许多针对这个非常大的蛋白质类别的可逆和不可逆抑制剂。其中，具有腈部分的分子，即易受酶亲核攻击的基团，已被鉴定为良好的抑制剂。尽管已知腈基团与 Cys25 共价结合，但关于该过程机制中涉及的能量学尚无报道。在此，进行了密度泛函理论和量子半经验计算，以研究含腈分子对半胱氨酸蛋白酶的分子识别。本文报道的结果表明，一种从 Cys25 到抑制剂的亲核攻击开始的相互作用，随后是 His162 的质子转移。仅检测到一个过渡态；然而，我们发现势能表面上存在能量平台。基于所提出的机制，讨论了一些可以提高含腈分子对半胱氨酸蛋白酶的生物学活性的结构特征。
