In Silico Investigation of Traditional Chinese Medicine for Potential Lead Compounds as SPG7 Inhibitors against
Kuen-Bao Chen1,2,3, Kuan-Chung Chen4, Ya-Lin Chang5
1Department of Bioinformatics and Medical Engineering, Asia University, Taichung 41354, Taiwan. d3510@mail.cmuh.org.tw.
Insights
Researchers identified Traditional Chinese Medicine compounds as potential inhibitors for paraplegin (SPG7) protein, offering new therapeutic leads for coronary artery disease (CAD). These compounds show promising binding affinities and stable interactions, paving the way for drug development.
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Coronary artery disease (CAD) is a leading global cause of mortality, linked to mitochondrial dysfunction and oxidative stress.
- A specific variant in the spastic paraplegia 7 (SPG7) gene has been associated with CAD, affecting protein processing.
- Paraplegin (SPG7) protein is a target for potential CAD therapeutics.
Purpose of the Study:
- To identify compounds from Traditional Chinese Medicines (TCMs) that can inhibit paraplegin (SPG7) activity.
- To explore novel therapeutic strategies for CAD by targeting the SPG7 protein.
Main Methods:
- Virtual screening of TCM compounds against the crystallographic structure of paraplegin.
- Prediction of disordered amino acid residues in the paraplegin binding site using PONDR-Fit.
- Molecular dynamics simulations to assess the stability of compound-protein interactions.
Main Results:
- Two TCM compounds, saussureamine C and 3-(2-carboxyphenyl)-4(3H)-quinazolinone, demonstrated potential binding affinities with paraplegin.
- Stable hydrogen bonds and hydrophobic interactions were observed between the candidate compounds and key paraplegin residues.
- Molecular dynamics simulations confirmed the stability of these interactions under dynamic conditions.
Conclusions:
- Saussureamine C and 3-(2-carboxyphenyl)-4(3H)-quinazolinone are proposed as potential lead compounds for paraplegin inhibitors.
- These TCM-derived compounds warrant further investigation for the development of novel drugs targeting 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.
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