In silico evaluation of bioactive compounds as dual inhibitors targeting ALK and EGFR for non-small cell lung cancer therapy.

Non-Small Cell Lung Cancer (NSCLC) is the most common type of lung cancer, accounting for around 85% of all lung cancer cases. Limitations of current therapeutics, including inefficient pharmacokinetics, poor selectivity, resistance development, and a lack of dual inhibitors, highlight the need for new drugs with improved efficacy and biocompatibility. This study used a comprehensive in silico approach against two major NSCLC targets, anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR), to identify potential dual inhibitors. After virtual screening of more than 12,200 bioactive compounds from the LC bioactive library, three compounds were selected based on ADME properties and docking scores against both targets: F6497-2232 (-8.808, -7.036), F3345-0499 (-8.575, -7.124), and F1011-0367 (-8.21, -8.045) with EGFR and ALK, respectively. The selected compounds were further evaluated through DFT, MM/GBSA, and 200 ns molecular dynamics simulations, including RMSD, RMSF, SASA, PSA, MolSA, Rg, electrostatic interactions, polar solvation energy, HOMO-LUMO gap, MEP, charge distribution, and total electronic energy analyses. PCA and DCCM analyses were performed to assess correlated and anticorrelated atomic motions and comparative biomolecular mobility over time. The compounds were also compared with brigatinib as an ALK inhibitor (docking score: -6.536) and lapatinib as an EGFR inhibitor (docking score: -7.229). Overall, the selected compounds showed stable binding, strong interaction networks, and favorable electronic and dynamic properties, suggesting their potential as dual ALK/EGFR inhibitors. This multitiered computational study provides a basis for further in vitro and in vivo validation in lung cancer therapeutic development.