Analysis of the structure of calpain-10 and its interaction with the protease inhibitor SNJ-1715

作者：da Silva Ronaldo Correia; de Alencar Nelson Alberto N; Alves Claudio Nahum; Lameira Jeronimo^*

来源：Computers in Biology and Medicine, 2013, 43(10): 1334-1340.

DOI：10.1016/j.compbiomed.2013.07.010

• Calpain-10
• Homology modelling
• QM/MM
• MD
• Inhibitor

Calpain-10 (CAPN10) is a cysteine protease that is activated by intracellular calcium (Ca2+) and known to be involved in diseases such as cancer, heart attack, and stroke. A role for the CAPN10 gene in diabetes mellitus type II was recently identified. Hyper activation of the enzyme initiates a series of destructive cycles that can cause irreversible damage to cells. The development of inhibitors may be useful as therapeutic agents for a number of calpainopathies. In this paper, we have used the homology modelling technique to determine the 3D structure of calpain-10 from Homo sapiens. The model of calpain-10 obtained by homology modelling suggests that its active site is conserved among family members and the main interactions are similar to those observed for mu-calpain. Structural analysis revealed that there are small differences in the charge distribution and molecular surface of the enzyme. These differences are probably less dependent on calcium for calpain-10 than they are for mu-calpain. In addition, the ion pair Cys(-)/His(+) formation was observed using of Molecular Dynamics (MD) simulations that were based upon hybrid quantum mechanical/molecular mechanical (QM/MM) approaches. Finally, the binding of the SNJ-1715 inhibitor to calpain-10 was investigated in order to further understand the mechanism of inhibition of calpain-10 by this inhibitor at the molecular level.

• 出版日期2013-10-1