Abstract
Coronary artery disease (CAD) is the most common cause of heart attack and the leading cause of mortality in the world. It is associated with mitochondrial dysfunction and increased level of reactive oxygen species production. According to the Ottawa Heart Genomics Study genome-wide association study, a recent research identified that Q688 spastic paraplegia 7 (SPG7) variant is associated with CAD as it bypasses the regulation of tyrosine phosphorylation of AFG3L2 and enhances the processing and maturation of SPG7 protein. This study aims to identify potential compounds isolated from Traditional Chinese Medicines (TCMs) as potential lead compounds for paraplegin (SPG7) inhibitors. For the crystallographic structure of paraplegin, the disordered disposition of key amino acids in the binding site was predicted using the PONDR-Fit protocol before virtual screening. The TCM compounds saussureamine C and 3-(2-carboxyphenyl)-4(3H)-quinazolinone, have potential binding affinities with stable H-bonds and hydrophobic contacts with key residues of paraplegin. A molecular dynamics simulation was performed to validate the stability of the interactions between each candidate and paraplegin under dynamic conditions. Hence, we propose these compounds as potential candidates as lead drug from the compounds isolated from TCM for further study in drug development process with paraplegin protein for coronary artery disease.
Highlights
Coronary artery disease (CAD), which can be called coronary atherosclerotic heart disease or ischemic heart disease, is the most common cause of heart attack, and one of the leading causes of mortality in the world [1,2,3,4]
The X-ray crystallography structure of the human associated with diverse cellular activities (AAA)+ protein paraplegin (SPG7) downloaded from RCSB Protein Data Bank with PDB ID: 2QZ4 [20] was employed as the target protein
The Traditional Chinese Medicines (TCMs) compounds were obtained from TCM Database@Taiwan [27], and each compound was prepared by Prepare Ligand module in DS 2.5 to protonate the molecular structure and filtered using Lipinski’s Rule of
Summary
Coronary artery disease (CAD), which can be called coronary atherosclerotic heart disease or ischemic heart disease, is the most common cause of heart attack, and one of the leading causes of mortality in the world [1,2,3,4]. The formation of multiple atheromatous plaques cause an artery wall thickens in a process called atherosclerosis [5]. The narrow arteries will restrict blood flow to the heart, increasing the risk of heart attack. Many studies indicate that mitochondrial dysfunction and increased reactive oxygen species production levels are associated with CAD [6,7,8,9,10,11].
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