AI-Driven Transfer Learning and Generative Model (TransGenGRU) Enables the Drug Discovery of Novel Natural Guaianolide Sesquiterpene Derivatives as Potent NLRP3 Inhibitors

The NLRP3 inflammasome is recognized as a critical mediator of innate immunity, which can regulate the maturation of proinflammatory cytokines. Nowadays, several natural products have been confirmed to exhibit potent NLRP3 inhibitory effects and possess novel binding mechanisms with NLRP3. Herein, an AI-driven model (TransGenGRU) is proposed to generate novel natural products with NLRP3 inhibitory activities. Through the modeling of TransGenGRU, two guaianolide sesquiterpenoids (A3 and A8) are identified to possess moderate NLRP3 inhibitory activities. Then, through detailed structure optimization, E1 demonstrates the most potent NLRP3 inhibitory activity (IC₅₀ = 24.42 nM), and the inhibitory effect on the NLRP3 inflammasome is correlated to the assembly of NLRP3/pro-caspase-1/ASC. Notably, E1 is confirmed to covalent-irreversibly interact with Cys280 that is totally different from MCC950. Besides, E1 also demonstrates potent anti-inflammatory activity in vivo, favorable DMPK profiles, and low hERG toxicity. Thus, E1 has been considered a novel and potent NLRP3 inhibitor.