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

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.

Residue-based design of small molecule inhibitor for H1N1, H5N1 and H7N1 mutants.

Point mutations H274Y and N294S can lead to resistance of influenza virus strains to some drug molecules. Recently, a large number of experiments has focused on the many frameworks and catalytic residues thought to prevent the efficacy of anti-flu drugs. In the past, most research has considered the role of drugs in rigid proteins rather than in flexible proteins. In this study, we used molecular dynamics simulation (MD) combined with structure- and ligand-based drug design (SBDD and LBDD) methods to study dynamic interaction and protein dynamics correlation statistics between compounds and both the framework and catalytic residues in influenza virus N1 strains. Drug candidates were screened using the IC50 of the docking result predicted by support vector machine, multiple linear regression, and genetic function approximation (P < 0.001). As shown by MD, saussureamine C and diiodotyrosine have a protein dynamics correlation similar to that of sialic acid, and both can participate in hydrogen bond formation with loop, framework, and catalytic residues. Our in silico findings suggest that saussureamine C can inhibit H274Y and N294S mutants, and that diiodotyrosine can also inhibit N294S mutants. Therefore, the drugs saussureamine C and diiodotyrosine have the potential to produce inhibitory effects on wild-type influenza virus and some N1 mutants.

Potent inhibitor design against H1N1 swine influenza: structure-based and molecular dynamics analysis for M2 inhibitors from traditional Chinese medicine database.

The rapid spread of influenza virus subtype H1N1 poses a great threat to million lives worldwide. To search for new anti-influenza compounds, we performed molecular docking and molecular dynamics simulation to identify potential traditional Chinese medicine (TCM) constituents that could block influenza M2 channel activity. Quinic acid, genipin, syringic acid, cucurbitine, fagarine, and methyl isoferulate all have extremely well docking results as compared to control amantadine. Further de novo drug design suggests that derivatives of genipin and methyl isoferulate could have enhanced binding affinity towards M2 channel. Selected molecular dynamics simulations of M2-derivative complexes show stable hydrogen bond interactions between the derivatives and M2 residues, Ser10 and Ala9. To our best knowledge, this is the first study on the anti-viral activity of the above listed TCM compounds.