Natural products (NPs) continue to serve as an invaluable source in drug discovery, and peripheral evolution of NPs is a highly efficient evolution strategy. Herein, we describe a unified "methyl to amide" peripheral evolution of Tanshinone IIA and Cryptotanshinone for discovery of NLRP3 inflammasome inhibitors. There were 54 compounds designed and prepared, while the chemoinformatic analysis revealed that these evolved NP analogues occupy a unique chemical space. Biological evaluation identified as an NLRP3 inflammasome inhibitor, and could directly bind to the NACHT domain of the NLRP3 protein and block the interaction of NLRP3 and ASC, thus suppressing ASC oligomerization and NLRP3 inflammasome assembly. Molecular dynamic stimulations revealed that the amide moiety played a vital role in the binding mode. Moreover, exhibited therapeutical efficacy in sepsis and the NASH mouse model. In conclusion, this protocol provides a new vision of NPs' peripheral evolution and a novel NLRP3 inflammasome inhibitor.
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