Molecular Docking and ADMET Prediction of Selected Neem (Azadirachta indica) Phytochemicals as EGFR Inhibitors: An Integrated In Silico Screening Study

Abstract

Background: The epidermal growth factor receptor (EGFR) tyrosine kinase is a clinically validated oncology drug target, yet acquired resistance and toxicity limit currently approved EGFR tyrosine kinase inhibitors (EGFR-TKIs) such as gefitinib and erlotinib. Azadirachta indica (neem), a plant deeply embedded in South Indian traditional medicine, is a rich source of limonoids and flavonoids reported to possess anticancer activity, making its constituents attractive candidates for computational anticancer screening. Objective: To priorities selected neem phytochemicals as candidate EGFR inhibitors through an integrated in silico workflow combining molecular docking, protein–ligand interaction profiling, drug-likeness and ADMET prediction. Methods: Twelve A. indica phytochemicals (six limonoids, three flavonoids, one flavanol, one phenolic acid and one phytosterol) plus gefitinib as the reference inhibitor were docked into the EGFR tyrosine kinase domain (five poses per ligand; 65 docking records including the reference). Poses were profiled for hydrogen-bond and hydrophobic contacts and for occupancy of the ATP-binding cleft (hinge Met793, gatekeeper Thr790, Cys797, Lys745, Asp855). Drug-likeness (Lipinski rule of five) and ADMET descriptors were predicted, and an integrated ranking assigned each compound a priority category. Results: Nimbolide showed the strongest binding among neem constituents (best docking energy −8.97 kcal/mol), approaching gefitinib (−9.34 kcal/mol), with zero Lipinski violations and high predicted gastrointestinal absorption, although it was flagged for predicted hepatotoxicity. Gedunin (−8.64), nimbandiol (−8.50), quercetin (−8.45) and kaempferol (−8.45 kcal/mol) were also strong binders engaging the EGFR hinge and gatekeeper similarly to gefitinib. Across the 65 poses, Thr790 (41 poses), Met793 (38) and Cys797 (37) were the most frequently contacted residues, indicating occupancy of the ATP-binding cleft. Large molecules (azadirachtin, rutin) bound well but violated Lipinski's rule. The integrated workflow prioritised nimbolide, and secondarily gedunin, as candidate EGFR-inhibitor scaffolds. Conclusion: This integrated screening prioritised nimbolide and gedunin as neem-derived candidate EGFR-inhibitor scaffolds.