Scaffold Hopping with Virtual Screening from IP3 to a Drug‐Like Partial Agonist of the Inositol Trisphosphate Receptor

Inositol 1,4,5‐trisphosphate (IP₃) is a universal signalling molecule that releases calcium from stores within cells by activating the IP₃ receptor. Although chemical tools that modulate the IP₃ receptor exist, none is ideal due to trade offs between potency, selectivity and cell permeability, and their chemical properties make them challenging starting points for optimisation. Therefore, to find new leads, we used virtual screening to scaffold hop from IP₃ by using the program ROCS to perform a 3D ligand‐based screen of the ZINC database of purchasable compounds. We then used the program FRED to dock the top‐ranking hits into the IP₃ binding pocket of the receptor. We tested the 12 highest‐scoring hits in a calcium‐release bioassay and identified SI‐9 as a partial agonist. SI‐9 competed with [³H]IP₃ binding, and reduced histamine‐induced calcium signalling in HeLa cells. SI‐9 has a novel 2D scaffold that represents a tractable lead for designing improved IP₃ receptor modulators.