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.
Highlights
The rhizomes and roots of aconitine species, a genus of the family Ranunculaceae, are commonly used in treatment for various illnesses such as collapse, syncope, rheumatic fever, joints pain, gastroenteritis, diarrhea, edema, bronchial asthma, and tumors. They are involved in the management of endocrinal disorders such as irregular menstruation [1,2]. The usefulness of this aconitine species component intermingles with toxicity after it is administered to a diseased patient
The 3D-quantitative structure–toxicity relationship (QSTR) contour maps were utilized to visualize the information on the comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)
The analysis of favorable and unfavorable regions of steric, electrostatic, hydrophobic, hydrogen bond donor (HBD), and hydrogen bond acceptor (HBA) atom fields contribute to the realization of the relationship between the aconitine alkaloid’s toxic activity and its structure
Summary
The rhizomes and roots of aconitine species, a genus of the family Ranunculaceae, are commonly used in treatment for various illnesses such as collapse, syncope, rheumatic fever, joints pain, gastroenteritis, diarrhea, edema, bronchial asthma, and tumors. It was evidenced that the aconitine component is the main active ingredient in this species’ root and rhizome, and is responsible for both therapeutic and toxic effects [8]. This medicinal has been tested for cancerological and dermatological activities. It was found to have an effect on postoperative analgesia [9,10,11,12]
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