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.