Repurposing terfenadine and domperidone for inhibition of apoptotic gene association in colorectal cancer: A system pharmacology approach integrated with molecular docking, MD simulations, and post-MD simulation analysis.

Abstract

Colorectal cancer (CRC) remains a leading cause of global cancer mortality, underscoring the need for novel therapeutic strategies. This study used a systems pharmacology approach integrated with molecular docking and molecular dynamics (MD) simulations to evaluate the potential of repurposing terfenadine and domperidone for inhibition of apoptotic gene associations in CRC. Network pharmacology analysis identified 4 principal targets-SLC6A4 (5I6X), DRD2 (7DFP), HTR2A (6WGT), and EGFR (6LUD)-involved in the apoptotic regulatory network. Molecular docking studies demonstrated high binding affinities of both terfenadine and domperidone against all selected targets (-7.1 to -11.5 kcal/mol), with the strongest interaction observed with DRD2, where both compounds exhibited a binding affinity of -11.5 kcal/mol. Detailed interaction profiling revealed critical hydrogen bonding and hydrophobic interactions stabilizing the drug-target complexes. Molecular dynamics simulations over a 100 ns timescale confirmed the structural stability and conformational fidelity of the docked complexes, evidenced by low root mean square deviation values and consistent hydrogen bond occupancy. Furthermore, post-MD simulation study supports the stable score landscape and stability of complex. In conclusion, this integrative computational analysis highlights terfenadine and domperidone as promising candidates capable of modulating key apoptotic pathways in CRC. The findings provide a strong rationale for subsequent in vitro and in vivo studies to validate their therapeutic potential and facilitate clinical translation in CRC management.