Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP₃R) Inhibitors in Cancer

Inositol 1, 4, 5-trisphosphate receptor (IP₃R)-mediated Ca²⁺ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca²⁺ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP₃-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP₃R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC₅₀) of a compound for IP₃R inhibition. Moreover, our GRIND model (PLS: Q² = 0.70 and R² = 0.72) further strengthens the identified pharmacophore features of IP₃R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6–8.0 Å and 6.8–7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP₃R modulators were used to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP₃R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca²⁺ signals in cancer.