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.

NLRP3炎性小体（NLRP3 inflammasome）被认为是固有免疫（innate immunity）的关键介导因子，可调控促炎细胞因子（proinflammatory cytokines）的成熟过程。目前已有多种天然产物（natural products）被证实具有强效的NLRP3抑制活性，且其与NLRP3的结合机制（binding mechanisms）独具新颖性。本文提出一种人工智能驱动的模型（TransGenGRU），用于生成具有NLRP3抑制活性的新型天然产物。通过TransGenGRU建模，研究者筛选出两种愈创木内酯类倍半萜（guaianolide sesquiterpenoids，A3与A8），其展现出中等强度的NLRP3抑制活性。经过细致的结构优化后，衍生物E1展现出最强的NLRP3抑制活性（半最大效应浓度IC50=24.42 nM），其对NLRP3炎性小体的抑制作用与NLRP3/半胱天冬酶-1前体（pro-caspase-1）/ASC的组装过程密切相关。值得注意的是，E1被证实可与Cys280位点发生共价不可逆结合，这与MCC950的作用机制完全不同。此外，E1在体内亦展现出强效抗炎活性，具备良好的药物代谢动力学（Drug Metabolism and Pharmacokinetics, DMPK）特性，且人类Ether-à-go-go相关基因（hERG）毒性较低。综上，E1可被认定为一种新型强效NLRP3抑制剂。