Rational design of an NLRP3 inhibitor with superior efficacy and safety for gout therapy

Gout, driven by urate crystal-induced inflammation, remains a therapeutic challenge due to the limited efficacy and toxicity of current treatments. Targeting the NLRP3 inflammasome, a central driver of gout pathogenesis, offers a promising strategy. While MCC950, a potent NLRP3 Inhibitor, demonstrated clinical potential, its discontinuation due to hepatotoxicity underscores the urgent need for safer alternatives. Here, we address these challenges through a rational drug design approach to develop next-generation NLRP3 inhibitors. By leveraging cryo-EM structures and molecular dynamics (MD) simulations of the MCC950-NLRP3 complex, we identified a structurally dynamic region near the furan moiety and an adjacent unoccupied hydrophobic pocket. Systematic structural optimization targeting this pocket enabled the design of M48, a derivative that exhibited superior anti-inflammatory activity (IC₅₀ = 11.9 nM), favorable oral bioavailability (89.7 % in rats), and an improved safety profile compared to MCC950. In an MSU-induced mouse gout model, M48 demonstrates superior anti-inflammatory and analgesic effects compared to indomethacin, with efficacy comparable to colchicine. The design strategy, grounded in computational insights into ligand-protein interactions, demonstrates both scientific rigor and broad applicability for optimizing small-molecule inhibitors. Notably, M48's enhanced efficacy and reduced liver toxicity risk validate the approach's potential for addressing unmet clinical needs in gout and Other NLRP3-associated diseases.

Conformational fluctuation optimization; Gout; Molecular dynamics simulations; NLRP3 inflammasome; Pharmacodynamic evaluation.