In Silico Investigation of Traditional Chinese Medicine for Potential Lead Compounds as SPG7 Inhibitors against Coronary Artery Disease

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.

Virtual screening and network pharmacology-based synergistic mechanism identification of multiple components contained in Guanxin V against coronary artery disease

“…TCM has a long history in clinical practice [59] and is gradually recognized at home and abroad [60]. CAD is the leading cause of mortality worldwide [61]. Great progress has been made in the treatment of CAD by TCM in recent years [62,63].…”

Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders

“…Tyrosine phosphorylation of paraplegin by AFG3L2 helps in paraplegin processing and inhibition of this processing can cause ROS production [ 111 ]. On the contrary, the Q688 variant of paraplegin can bypass the tyrosine phosphorylation regulation of AFG3L2 [ 112 ]. Another type of SCAR found by Calandra and co-workers includes two novel AFG3L2 heterozygous mutations (W128* and R695G) that cause spastic ataxia with unique eye-of-the-tiger pattern that can be related to iron deposition and pantothenate kinase-related neurodegeneration that affects CoA synthesis pathway [ 18 ].…”

Traditional Chinese Medicine for Coronary Artery Disease Treatment: Clinical Evidence From Randomized Controlled Trials

“…Mortality related to cardiovascular diseases is also rapidly escalating worldwide and brings a great threat to global health (4). Either incidence or mortality of coronary artery disease (CAD) accounts for a large part of cardiovascular diseases (5)(6)(7). In the United States, CAD accounts for more than two-thirds of all cardiovascular diseases, and almost half of Americans have at least one risk factor (8).…”