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Scaffold Hopping with Virtual Screening from IP 3 to a Drug‐Like Partial Agonist of the Inositol Trisphosphate Receptor
Author(s) -
Vasudevan Sridhar R.,
Singh Nisha,
Churchill Grant C.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402440
Subject(s) - receptor , partial agonist , agonist , inositol , virtual screening , calcium , chemistry , pharmacophore , biophysics , biology , biochemistry , organic chemistry
Inositol 1,4,5‐trisphosphate (IP 3 ) is a universal signalling molecule that releases calcium from stores within cells by activating the IP 3 receptor. Although chemical tools that modulate the IP 3 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 IP 3 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 IP 3 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 [ 3 H]IP 3 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 IP 3 receptor modulators.