Multitargeted molecular docking and dynamics simulation of thymol-based chalcones against cancer protein markers: Synthesis, characterization, and computational study

Cancer prevention has become a significant public health concern in the 21st century, ranking as the second leading cause of global mortality following cardiovascular diseases. Despite prominent advancements in treatment, addressing cancer remains a substantial public health challenge, necessitating precise interventions tailored to diverse cancer types. The targeting of Epidermal Growth Factor Receptor (EGFR) has emerged as a fundamental strategy in modern cancer therapy due to its critical role in oncogenesis. Chalcones, a subclass of flavonoids, are promising anticancer agents due to their ability to target multiple cellular pathways implicated in cancer progression. The presence of α, β-unsaturated carbonyl moiety is a key structural feature attributed to their biological activity. This study presents an efficient synthesis approach for chalcone derivatives 4a-f designed from natural thymol. The synthesized compounds were further characterized by HRMS, ¹H and ¹³C NMR spectral data, and further evaluated for in silico studies through molecular docking, molecular dynamic simulation, and ADMET screening. All the designed compounds 4a-f displayed favourable physicochemical properties and ADMET profiles. Molecular docking revealed favourable interactions between compounds 4a-f and the EGFR target protein. Compound 4d (p-nitro) and 4b (p-methyl) showed the more favourable docking score with low energy conformation (-8.02 kcal/mol), (-7.42 kcal/mol) respectively compared to the standard drug Gefitinib. Molecular dynamic simulations confirmed the stability of compounds 4d and 4b, exhibiting consistent structural stability in ligand-protein complexes throughout the 100 ns simulation. Acceptable RMSF values for amino acid residues indicated structural integrity and a stable protein-ligand interaction. The study identified 4d and 4b as promising leads for targeting EGFR.