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.

Marine animals and plants provide abundant secondary metabolites with antitumor activity. Itampolin A is a brominated natural tyrosine secondary metabolite that is isolated from the sponge Iotrochota purpurea. Recently, we have achieved the first total synthesis of this brominated tyrosine secondary metabolite, which was found to be a potent p38α inhibitor exhibiting anticancer effects. A fragment-based drug design (FBDD) was carried out to optimize itampolin A. Forty-five brominated tyrosine derivatives were synthesized with interesting biological activities. Then, a QSAR study was carried out to explore the structural determinants responsible for the activity of brominated tyrosine skeleton p38α inhibitors. The lead compound was optimized by a FBDD method, then three series of brominated tyrosine derivatives were synthesized and evaluated for their inhibitory activities against p38α and tumor cells. Compound 6o (IC₅₀ = 0.66 μM) exhibited significant antitumor activity against non-small cell lung A549 cells (A549). This also demonstrated the feasibility of the FBDD method of structural optimization.

Novel N-substituted tetrahydro-β-carboline imidazolium salt derivatives proved to have potent antitumor activity in past research. The Topomer CoMFA and CoMSIA function in Sybyl-X 2.0 software was applied for the identification of important features of N-substituted tetrahydro-β-carboline-imidazolium salt derivative moieties. In the case of Topomer CoMFA, all the compounds were split into two fragments which were used to generate a 3D invariant representation, the statistical results of the Topomer CoMFA model: q² value of 0.700; r² value of 0.954; with 5 optimum components. The database alignment was utilized for building the CoMSIA model, and the CoMSIA model had q² and r² values of 0.615 and 0.897, with 4 optimum components. Target fishing of the PharmMapper platform was utilised for finding potential targets, the human mitogen-activated protein kinase 1 (MEK-1) was found to be the primary potential target for the three compounds with the fit scores of 6.288, 5.741, and 6.721. The molecular docking technique of MOE 2015 was carried out to identify the interactions of amino acids surrounding the ligand, and correlating QASR contour maps were used to identify structural requirements of N-substituted tetrahydro-β-carboline imidazolium salt moieties. Molecular dynamics and simulation studies proved that the target protein was stable for 0.8–5 ns. The pivotal moieties of N-substituted tetrahydro-β-carboline imidazolium salt derivatives and its potential targets were verified by the QASR study, PharmMapper, and the molecular docking study which would be helpful to design novel MEK-1 inhibitors for anticancer drugs.

A series of imidazolium salt derivatives have demonstrated potent antitumor activity in prior research. A comprehensive in silicon method was carried out to identify the putative protein target and detailed structure-activity relationship of the compounds. The Topomer CoMFA and CoMSIA techniques were implemented during the investigation to obtain the relationship between the properties of the substituent group and the contour map of around 77 compounds; the Topomer CoMFA and CoMSIA models were reliable with the statistical data. The protein–protein interaction network was constructed by combining the Pharmmapper platform and STRING database. After generating the sub-network, the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA with protein data bank ID: 3ZIM) was selected as the putative target of imidazolium salt derivatives. A docking study was carried out to correlate interactions of amino acids in protein active pockets surrounded by the ligand with contour maps generated by the structure-activity relationship method. Then the molecular dynamics simulations demonstrated that the imidazolium salt derivatives have potent binding capacity and stability to receptor 3ZIM, and the two ligand-receptor complex was stable in the last 2 ns. Finally, the ligand-based structure-activity relationship and receptor-based docking were combined together to identify the structural requirement of the imidazolium salt derivatives, which will be used to design and synthesize the novel PIK3CA inhibitors.