Investigation of BTK as a Potent Immunomodulatory Target: Exploring Novel Therapeutic Approaches for Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by progressive neurological impairment. Bruton's tyrosine kinase (BTK) has emerged as a crucial therapeutic target due to its role in B-cell activation and innate immune signaling. While BTK inhibitors (BTKi) have shown promise for treating MS and inflammatory disorders, their high toxicity and off-target kinase inhibition pose challenges, particularly given that many patients experience mild symptoms. This study presents , a structurally optimized, highly selective BTKi designed to minimize drug-induced liver injury (DILI) and improve blood-brain barrier (BBB) permeability. Using scaffold hopping, the nitro-substituted aromatic scaffold was replaced with a trifluoromethyl-substituted heterocycle, significantly reducing hepatotoxicity while enhancing binding interactions with key BTK residues (CYS481, GLY480, and ASP539). also demonstrates lower CYP inhibition, reduced AMES toxicity, and improved membrane absorption, ensuring better druggability. Computational analyses, including site-directed mutation studies, molecular dynamics (MD) simulations, and quantum chemical analysis, confirmed 's high binding specificity, reduced off-target effects, and strong conformational stability across BTK variants. mitigates off-target effects through structural optimization of the BTK binding pocket, particularly at CYS481, enhancing binding specificity and reducing nonspecific interactions across BTK mutants. These findings establish as a next-generation BTKi with enhanced safety and therapeutic potential for autoimmune and inflammatory diseases, particularly MS.