Synthesis of novel (R)-Carvone-1,2,3-triazole hybrids: Network pharmacology, molecular docking, and dynamics simulation targeting tumor protein markers

Cancer poses a global health crisis with increasing incidence and mortality rates, urging the development of novel anti-cancer therapies. 1,2,3-triazoles, recognized for their diverse biological activities, offer promising avenues for drug discovery targeting critical proteins associated with various cancer types. In this study, various derivatives of 1,2,3-triazoles were synthesized and their anti-cancer potential was tested under both in-silico and in-vitro conditions. The synthesized derivatives 9a-h show IC₅₀ values in the range of 25–100 µM against various cancer cell lines. Incorporating the 4-nitro-phenyl group at the N1 position of the triazole nucleus 9d resulted in increased activity compared to other synthesized 1,2,3-triazoles against HT-1080 and MCF-7. A network pharmacology study was conducted to predict the breast cancer targets of the synthesized regioisomers. The results indicate that the proteins SRC, MYC, and HSP90AA1 are most likely the breast cancer targets of the synthesized compounds. To study the binding effect of synthesized compounds on the selected targets, a molecular docking study was conducted and it revealed that both synthesized compounds have good binding affinity towards SRC (< -7.0 kcal/mol). Also, the synthesized compounds showed no violations at any of the drug-likeness filters during the ADME study. Finally, molecular dynamics simulation was carried out to determine the stability of interaction between the protein and ligand for a 200 ns duration. The SRC complexed with compound 9d showed more stability during MD simulation with few interactions being maintained throughout the simulation time. Therefore, compound 9d could be a promising drug candidate for cancer chemotherapy.