Identification of Marine Compounds Inhibiting NF-κBInducing Kinase Through Molecular Docking and Molecular Dynamics Simulations

Abstract

NF-κB-inducing kinase (NIK) plays a pivotal role in regulating both the canonical and non-canonical NF-κB signaling pathways, driving the expression of proteins involved in inflammation, immune responses, and cell survival. Overactivation of NIK is linked to various pathological conditions, including chronic inflammation, autoimmune diseases, metabolic disorders, and cancer progression. As such, NIK represents a compelling target for therapeutic intervention in these diseases. In this study, we explored the inhibitory potential of marine-derived compounds against NIK using integrated computational techniques, including molecular docking, molecular dynamics (MD) simulations, and free energy calculations. By screening a library of bioactive marine compounds, we identified several promising candidates with strong binding affinity to the NIK active site. By continuously narrowing down the library at each step, we found that the compounds santacruzamate A, xanthosine, and actinonine stand out at each step by demonstrating compact binding, highly stable interactions, and the most favorable free energy profiles, indicating their potential as effective NIK inhibitors. These findings not only advance our understanding of marine compounds as valuable resources for drug discovery but also highlight their potential for the development of natural anti-inflammatory therapies targeting NIK. This study opens new avenues for future research and therapeutic development aimed at combating inflammation and cancer through NIK inhibition.