In Silico Novel Luteolin Derivatives Targeting Egfr in Non-Small Cell Lung Cancer Compared With Erlotinib

Luteolin, a natural flavonoid abundantly present in Lawsonia inermis (Henna), exhibits anticancer activity by regulating key pathways including EGFR, PI3K/Akt, and MAPK. However, its clinical translation is limited by moderate EGFR affinity, low permeability, and rapid metabolism. This study applies rational Structure–Activity Relationship (SAR)-guided design to generate 12 novel luteolin derivatives and screen them for enhanced efficacy against Epidermal Growth Factor Receptor (EGFR), a major target in Non-Small Cell Lung Cancer (NSCLC). Ligands were designed in MolView, docked using SwissDock (Attracting Cavities 2.0), and evaluated for ADMET using SwissADME and toxicity using ProTox-3.0. Among all derivatives, 7-O-(4-pyridylmethyl)-3’,4’-dichloro-5-O-phosphono-luteolin achieved the best binding score (−8.2684 kcal/mol), surpassing natural luteolin (−6.5928) and nearing Erlotinib (−7.6802). ADMET profiling confirmed high GI absorption, moderate lipophilicity, good drug-likeness, and low toxicity (Class 5). Mechanistic pathway mapping indicated that this compound potentially inhibits EGFR downstream signalling (RAS/RAF/MEK/ERK and PI3K/Akt), similar to clinically approved EGFR-TKIs. Thus, the designed derivative presents a promising scaffold for EGFR-targeted therapy in NSCLC.