Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer
Inositol 1, 4, 5-trisphosphate receptor (IP<sub>3</sub>R)-mediated Ca<sup>2+</sup> signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca<sup>2+</sup> signals by targeting the downstream effectors...
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12993 |
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| author | Humaira Ismatullah Ishrat Jabeen |
| author_facet | Humaira Ismatullah Ishrat Jabeen |
| author_sort | Humaira Ismatullah |
| collection | DOAJ |
| description | Inositol 1, 4, 5-trisphosphate receptor (IP<sub>3</sub>R)-mediated Ca<sup>2+</sup> signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca<sup>2+</sup> 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 IP<sub>3</sub>-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP<sub>3</sub>R 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 (IC<sub>50</sub>) of a compound for IP<sub>3</sub>R inhibition. Moreover, our GRIND model (PLS: Q<sup>2</sup> = 0.70 and R<sup>2</sup> = 0.72) further strengthens the identified pharmacophore features of IP<sub>3</sub>R 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 IP<sub>3</sub>R 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 IP<sub>3</sub>R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca<sup>2+</sup> signals in cancer. |
| first_indexed | 2024-03-10T04:52:14Z |
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| language | English |
| last_indexed | 2024-03-10T04:52:14Z |
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| spelling | doaj.art-5c245d1f8c5a4dff894050e610dbeec42023-11-23T02:31:28ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231299310.3390/ijms222312993Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in CancerHumaira Ismatullah0Ishrat Jabeen1Research Centre for Modelling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, PakistanResearch Centre for Modelling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, PakistanInositol 1, 4, 5-trisphosphate receptor (IP<sub>3</sub>R)-mediated Ca<sup>2+</sup> signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca<sup>2+</sup> 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 IP<sub>3</sub>-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP<sub>3</sub>R 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 (IC<sub>50</sub>) of a compound for IP<sub>3</sub>R inhibition. Moreover, our GRIND model (PLS: Q<sup>2</sup> = 0.70 and R<sup>2</sup> = 0.72) further strengthens the identified pharmacophore features of IP<sub>3</sub>R 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 IP<sub>3</sub>R 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 IP<sub>3</sub>R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca<sup>2+</sup> signals in cancer.https://www.mdpi.com/1422-0067/22/23/12993IP<sub>3</sub>R-mediated Ca<sup>2+</sup> signalingIP<sub>3</sub>R modulatorspharmacophore modelingvirtual screeninghitsGRIND model |
| spellingShingle | Humaira Ismatullah Ishrat Jabeen Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer International Journal of Molecular Sciences IP<sub>3</sub>R-mediated Ca<sup>2+</sup> signaling IP<sub>3</sub>R modulators pharmacophore modeling virtual screening hits GRIND model |
| title | Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer |
| title_full | Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer |
| title_fullStr | Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer |
| title_full_unstemmed | Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer |
| title_short | Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP<sub>3</sub>R) Inhibitors in Cancer |
| title_sort | combined pharmacophore and grid independent molecular descriptors grind analysis to probe 3d features of inositol 1 4 5 trisphosphate receptor ip sub 3 sub r inhibitors in cancer |
| topic | IP<sub>3</sub>R-mediated Ca<sup>2+</sup> signaling IP<sub>3</sub>R modulators pharmacophore modeling virtual screening hits GRIND model |
| url | https://www.mdpi.com/1422-0067/22/23/12993 |
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