Multi-omics network pharmacology and computational validation reveal amodiaquine and desethylamodiaquine as apoptosis-regulating multi-target candidates in colon adenocarcinoma.

One of the biggest causes of cancer-related mortality worldwide is still colon adenocarcinoma (COAD). Therefore, it is essential to investigate new therapy strategies. This study presents a multi-scale, hypothesis-generating framework that integrates network pharmacology with multi-omics data and quantum chemical analyses to systematically explore the repositioning potential of amodiaquine and desethylamodiaquine in colon adenocarcinoma. Eleven gene targets that were found to be shared across medication, gene expression, and illness databases included several computationally significant central hub genes with high network centrality, including BTK, SIGMAR1, SYK, and KCNH2. Amodiaquine and Desethylamodiaquine both showed high binding scores (-7.9 to -12.6 kcal·mol⁻¹) across all the selected proteins. The protein-ligand complexes' structural stability was confirmed by molecular dynamic simulations lasting more than 100 ns; RMSD, RMSF, and radius of gyration analyses collectively indicate that the protein-ligand complexes maintain structural stability, compactness, and limited conformational fluctuation throughout the simulation, reflecting preserved protein integrity rather than direct binding strength. While density functional theory investigations indicated stable geometries with high electronic polarizability, MM-PBSA calculations yielded binding free energies within a range of ΔG_bind = -59.0 to -67.0 kcal·mol⁻¹ . These results suggest that amodiaquine derivatives have anti-COAD actions due to their disruption of important immune-regulatory and apoptotic pathways. These findings computationally prioritize amodiaquine and desethylamodiaquine as candidate multi-target interactors in colon adenocarcinoma, warranting further experimental investigation rather than implying established therapeutic efficacy.