A Comprehensive In Silico Method to Study the QSTR of the Aconitine Alkaloids for Designing Novel Drugs

Abstract

A combined in silico method was developed to predict potential protein targets that are involved in cardiotoxicity induced by aconitine alkaloids and to study the quantitative structure–toxicity relationship (QSTR) of these compounds. For the prediction research, a Protein-Protein Interaction (PPI) network was built from the extraction of useful information about protein interactions connected with aconitine cardiotoxicity, based on nearly a decade of literature and the STRING database. The software Cytoscape and the PharmMapper server were utilized to screen for essential proteins in the constructed network. The Calcium-Calmodulin-Dependent Protein Kinase II alpha (CAMK2A) and gamma (CAMK2G) were identified as potential targets. To obtain a deeper insight on the relationship between the toxicity and the structure of aconitine alkaloids, the present study utilized QSAR models built in Sybyl software that possess internal robustness and external high predictions. The molecular dynamics simulation carried out here have demonstrated that aconitine alkaloids possess binding stability for the receptor CAMK2G. In conclusion, this comprehensive method will serve as a tool for following a structural modification of the aconitine alkaloids and lead to a better insight into the cardiotoxicity induced by the compounds that have similar structures to its derivatives.

Involvement of Nrf2-HO-1/JNK-Erk Signaling Pathways in Aconitine-Induced Developmental Toxicity, Oxidative Stress, and ROS-Mitochondrial Apoptosis in Zebrafish Embryos

“…The presence of extracellular sodium, induced by AC, caused the reduced inactivation of the alpha subunits of the human heart (hH1) channels ( Wright, 2002 ). Wang et al reported that AC possessed binding stability for the receptor calcium-calmodulin–dependent protein kinase gamma (CAMK2G) ( Wang et al, 2018 ). Sun’s results indicated that AC significantly aggravated Ca 2+ overload and caused arrhythmia and finally promotes apoptotic development via phosphorylation of P38 mitogen-activated protein kinase ( Sun et al, 2014 ).…”

Ortholog genes from cactophilic Drosophila provide insight into human adaptation to hallucinogenic cacti

“…Our detection of ALDH2 is interesting as this gene is not only associated with alcohol dependence in humans, but is also an important regulator of dopaminergic and serotonergic systems implicated in protective effects against opioids addiction 48 and exhibits important interactions with the mescaline receptor 5-HT2A, responsible of the psychotropic effects and involved Reference populations: www.nature.com/scientificreports/ in several mental pathologies 49,50 . The expression of ATP2A1 has been related to the induced cardiotoxicity of alkaloids, suggesting an important role in maintaining calcium homeostasis during cardiac arrhythmia 51,52 , while CYP3A genes, members of the P-450 family gene, encode for one of the most important CYP isoforms (CYP3A4, CYP3A5, CYP3A7 and CYP3A43) responsible of alkaloids detoxification and clearance of psychotropic medication in humans 53,54 . These findings are in line with our detection of several psychotropic and toxic alkaloids in T. terscheckii.…”

Antitumor effects of aconitine in A2780 cells via estrogen receptor β‑mediated apoptosis, DNA damage and migration

“…aconitine ( Fig. 1a), also known as monkshood or devil's helmet, is a type of toxin produced by the aconitum plant that has been used as a traditional medicine in china due to its analgesic and anti-inflammatory effects (32). A previous study has indicated that aconitine can induce apoptosis in human pancreatic cancer cells via the nF-κB signaling pathway (33).…”