Computational Investigation of Eugenol–triazole Derivatives Targeting Breast Cancer Proteins

Abstract

Aims: The present study aimed to evaluate the binding affinity and interaction profiles of the newly designed eugenol-triazole derivatives against key breast cancer- associated protein targets using molecular docking, to identify promising lead compounds for anti-breast cancer drug development. Study Design:  Computational in silico molecular docking study. Place and Duration of Study: All molecular modeling studies were conducted using the Schrodinger Maestro software. Methodology: A total of 35 designed eugenol-triazole derivatives were selected as ligands for the structure-based molecular docking (SBDD) studies against key breast cancer targets retrieved from the Protein Data Bank, including (PDB IDs: 2IOG, 1SQN, 1M17, 5DXT, and 4DRH). Molecular docking simulations were performed using Schrodinger Maestro software. Binding affinities were evaluated based on docking scores. The performance of the designed eugenol-triazole derivatives was compared with co-crystallized ligands along with reference standards for each target. Results: Numerous eugenol-triazole derivatives demonstrated favorable docking scores and stable binding conformations within the active sites of selected breast cancer-related protein targets. The primary interactions involved hydrogen bonding with crucial active-site residues and π–π stacking interactions, attributed mainly to the presence of the triazole moiety. In multiple targets, the binding affinities selected derivatives were comparable to or better than those of standard reference ligands, indicating protein-ligand complementarity. Conclusion: Among the designed compounds Tria-23 (-8.976 kcal/mol, Erα, PDB ID: 2IOG), Tria-8 (-10.102, PR, PDB ID: 1SQN), Tria-25 (-7.637 and -5.434, EGFR and mTOR, PDB IDs: 1M17, and 4DRH), and Tria-24 (-6.808, PI3Kα, PDB ID: 5DXT) emerged as most potential lead molecules. Incorporation of the triazole ring enhanced molecular interactions and binding stability within the target active sites. These results provide a strong computational rationale for further in vitro and in vivo biological evolution of the designed compounds as potential anti-breast cancer agents.