Structure-Guided Design of 2-Amino-4-Phenylthiazole Derivatives Targeting EGFR: DFT Insights and Molecular Docking Evaluation

Abstract Background: Breast cancer is the second leading cause of cancer-related deaths among women globally. Tubulin polymerase is a well-established target in anticancer therapy due to its role in cell division. This study aimed to design and evaluate novel N-2-(4-(4-substituted phenyl) thiazol-2-ylamino) acetamide derivatives as potential tubulin polymerase inhibitors. Methods: Compounds were designed based on structure–activity relationship (SAR) insights and evaluated for drug-likeness using QikProp (ADMET analysis). Molecular docking was performed using AutoDock targeting the tubulin polymerase binding site (PDB ID: 3HKD), followed by molecular dynamics (MD) simulations and MM-GBSA free binding energy analysis using Desmond. The anticancer activity of synthesized compounds was assessed using the sulforhodamine B (SRB) assay against the MDA-MB-231 breast cancer cell line. Results: Docking scores ranged from − 6.501 to − 9.616 kcal/mol, with compound 5A showing the strongest binding, attributed to hydrogen substitution on the phenyl ring and a 4-bromine group on the acetamide scaffold. MD and MM-GBSA studies confirmed the stability and favorable binding energy of compound 5A. All compounds displayed acceptable physicochemical and ADMET properties. Six derivatives exhibited cytotoxicity comparable to Adriamycin (10 µM), indicating potent anticancer activity. Conclusion: The synthesized thiazole-based derivatives, particularly compound 5A, demonstrate significant potential as tubulin polymerase inhibitors. These findings support further development of this scaffold as a lead for novel anticancer agents.