In silico evaluation of (benzo)chromeno[3,4-c]pyridine derivative as dual EGFR/HER2 inhibitors for non-small cell lung cancer

(Benzo)chromeno[3,4-c]pyridine derivatives continue to attract significant scientific interest due to their broad pharmacological relevance, especially in cancer chemotherapy. In this study, both experimental and density functional theory (DFT) based computational approaches were employed to investigate the structural, electronic, spectroscopic, and anticancer potential of synthesized (benzo)chromeno[3,4-c]pyridine derivative. Experimentally, the compounds were successfully synthesized and confirmed using FT-IR and NMR spectroscopy, where the correlation between experimental and theoretical vibrational frequencies showed strong linear agreement (R² = 0.7141). Theoretical geometry optimization validated the structural stability of the molecules, while frontier molecular orbital (FMO) analysis revealed low HOMO-LUMO energy gaps ranging from 2.72 to 4.35 eV, indicative of high chemical reactivity and potential bioactivity. Molecular Electrostatic Surface Potential (MESP) mapping and natural bond orbital (NBO) analyses identified electrophilic and nucleophilic centers primarily localized around heteroatoms and conjugated π-systems, suggesting favorable interaction patterns with receptor active sites. Molecular docking against NSCLC-related therapeutic targets demonstrated strong binding affinities, with binding energies ranging from - 7.0 to - 11.0 kcal/mol, mediated by conventional hydrogen bonds, π-π stacking, and hydrophobic interactions within the ligand-binding domains. ADMET predictions further indicated favorable pharmacokinetic behavior, including high gastrointestinal absorption, non-inhibitory profiles for major CYP450 isoforms, and acceptable toxicity scores, highlighting their suitability as orally bioavailable drug candidates. Collectively, the synergy between experimental characterization and computational modeling demonstrates that (benzo)chromeno[3,4-c]pyridine derivative possess promising structural, electronic, and pharmacokinetic properties, positioning them as strong therapeutic candidates for further development against non-small cell lung cancer. Additional biological assays and structural optimization are recommended to advance these compounds toward preclinical evaluation.