Triazine–Salicylate–Aniline Hybrids as Potential Anticancer Agents: Virtual Molecular Hybridization, ADMET, Molecular Docking, Molecular Dynamics, MMGBSA and DFT Studies

Breast cancer is one of the diseases responsible for about 2 to 3 million deaths globally. Considering the negative health and social and economic impacts associated with this disease, there is an urgent need to develop new drugs which can ultimately cure this disease. In the present study, we have explored a new series of fifteen 1,3,5‐triazine, salicylate and aniline hybrids 7a-o as potential anticancer agents through computational analysis. In silico ADMET, molecular docking and dynamics, MMGBSA and DFT‐based studies were used to predict safety, efficacy, binding affinity, interactions and stability of ligands 7a-o in the active site of the target EGFR and HER2 enzymes. All target triazine–salicylate–aniline 7a–o hybrids did not violate the Lipinski rule with acceptable pharmacokinetic and toxicity properties and were presumed safe for further studies. Molecular docking revealed that compounds 7c , 7f , 7i , 7l and 7o , with ethylene diamine substituent at the R1 position, had the most favourable binding energy against the HER2‐breast cancer cell line, ranging from −8.01 to −10.15 kcal/mol, suggesting that the ethylenediamine group plays a crucial role at the pharmacophore. The estimated binding‐free energy from MMGBSA analysis and molecular dynamics simulation showed that these hybrids are stabilized at low energy levels with supporting evidence from root‐mean‐square deviation (RSMD) and root‐mean‐square fluctuation (RSMF). DFT results further indicated that the relative activity of the hybrids 7c , 7f, 7i , 7l and 7o is not primarily due to their intrinsic electronic properties but rather due to their interactions with the EGFR and HER2 growth factors, which is important in the development of new potent anticancer agents.