Unveiling mechanism of action of alkaloids from Macleaya microcarpa as NF-κB inhibitors for gastric cancer: Insights from network pharmacology, molecular docking, dynamics simulations and ADMET prediction

Abstract

Gastric cancer, a highly aggressive malignancy, ranks fifth globally in new cases and deaths in 2022. Natural products from traditional Chinese medicine exhibit potential in cancer therapy. This study investigated the mechanism of benzophenanthridine alkaloids from Macleaya microcarpa as potential anti-gastric cancer agents, targeting the NF-κB-inducing kinase (NIK, protein ID: 4G3F). The results indicated that CPD1 likely modulates the non-canonical NF-κB pathway, with molecular docking revealing a superior binding energy (-9.86 kcal/mol) compared to IMD 0354 (-7.61 kcal/mol). Molecular dynamics simulations over 100 ns confirmed stable interactions, with RMSD ranging from 0.20 to 0.25 nm, Rg around 2.1 nm, and SASA from 150 to 165 nm², supporting a robust binding profile. In silico ADMET analysis demonstrated high intestinal absorption, limited distribution, CYP3A4 metabolism, and a good clearance rate, with no AMES toxicity. These results position CPD1 as a promising NIK inhibitor for gastric cancer therapy.