The paper explores annomontine's anticancer potential through ADMET profiling, DFT analysis, target prediction, molecular docking, and cytotoxicity testing on cancer cells.

Abstract

EGFR is an important target for cancer treatment owing to its role in tumor growth and resistance. Annomontine alkaloids show anticancer potential, but their EGFR inhibition remains underexplored. This study aimed to test a set of annomontine-derived compounds as anticancer agents against EGFR utilizing a mixture of computational and in-vitro methods. Twenty three annomontine derivatives were designed and optimized using DFT. In-silico methodologies like docking, simulation, and ADMET were employed to assess their binding affinity to EGFR with pharmacokinetic properties, prediction and cytotoxicity was confirmed via in vitro. Docking studies revealed P3F (−9.45 kcal/mol), P3H (−9.65 kcal/mol), and P3G (−9.39 kcal/mol) as the best hit compounds, superior to the activity of FDA-approved EGFR inhibitors such as osimertinib (−6.32 kcal/mol), toceranib (−7.98 kcal/mol). MD confirmed the integrity of the protein–ligand contacts, while ADMET profiling showed good solubility, permeability, and low toxicity. Cytotoxicity assays revealed that P3F (IC₅₀ = 0.26 µM) and P3H (IC₅₀ = 0.37 µM) exhibit greater potency than reference drugs. These findings suggest that P3F and P3H are promising candidates for the development of second-generation EGFR inhibitors, combining strong binding, favorable pharmacokinetics, and superior anticancer activity.