Probing the Pharmacological Mechanisms and Optimization of NIK Inhibitor Via Gaussian Accelerated Molecular Dynamics Simulations

Abstract The emergence of autoimmune diseases represents a pressing concern, with NF‐κB assuming a pivotal role as a mediator of immune regulation. It exerts substantial regulatory influence over both innate and adaptive immunity. NIK, an upstream protein of NF‐κB2, triggers aberrant activation of the non‐canonical NF‐κB signaling pathway upon overexpression, thereby influencing the onset and advancement of various autoimmune diseases. Consequently, exploring small molecule inhibitors aimed at NIK presents significant promise. This study utilized Gaussian accelerated dynamics simulations to investigate the interaction mechanism between the compound m1 of Amgen and the NIK protein. Based on the dynamic findings, m1 underwent optimization and modification. The modified molecules were individually subjected to 500 ns Gaussian accelerated dynamics simulations, mirroring those conducted for the complex system comprising compound m1 the NIK protein, and the unbound ligand NIK protein. Subsequently, the simulation results were juxtaposed with those of the NIK‐m1 system to discern the rationale behind the optimization direction. The optimized molecules were synthesized, and their biological activity was assessed to yield active compounds exhibiting enhanced physicochemical properties. This study offers valuable insights for the development of improved NIK inhibitors.