Virtual screening-led design of inhibitor scaffolds for the NLRP3 inflammasome

[Display omitted] •New inhibitors of NLRP3 inflammasome identified by virtual screening and MD simulation.•The most potent inhibitors inhibit IL-1β release with IC50 of 1 – 4 μM.•Novel scaffolds combining sulfonamide group with indole, benzofuran or tricyclic 6,7-dihydro-5H-indeno[5,6-b]furan ring. The NLRP3 inflammasome is a key target for drug discovery due to its implication in a range of inflammation-related diseases. In this work, we identify new inhibitors of the NLRP3 inflammasome via a hierarchical virtual screening strategy using molecular similarity, docking and MD simulation. The most potent inhibitors identified from a subsequent biological assay (IC50 of 1 – 4 μM) feature a sulfonamide group, a motif known to favour NLRP3 inhibition, in conjunction with an indole, benzofuran or tricyclic 6,7-dihydro-5H-indeno[5,6-b]furan ring, yielding novel scaffolds. These structures provide a basis for the design of more potent, selective NLRP3 inhibitors.