{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T03:28:52Z","timestamp":1775186932646,"version":"3.50.1"},"reference-count":137,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T00:00:00Z","timestamp":1638230400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u00c5 and 4.79 \u00c5) and two hydrogen-bond donors (5.56 \u00c5 and 7.68 \u00c5), 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\u20138.0 \u00c5 and 6.8\u20137.2 \u00c5, 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.<\/jats:p>","DOI":"10.3390\/ijms222312993","type":"journal-article","created":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T22:01:11Z","timestamp":1638309671000},"page":"12993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP3R) Inhibitors in Cancer"],"prefix":"10.3390","volume":"22","author":[{"given":"Humaira","family":"Ismatullah","sequence":"first","affiliation":[{"name":"Research Centre for Modelling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6660-6764","authenticated-orcid":false,"given":"Ishrat","family":"Jabeen","sequence":"additional","affiliation":[{"name":"Research Centre for Modelling and Simulation (RCMS), National University of Sciences and Technology (NUST), Sector H-12, Islamabad 44000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Shapovalov, G., Ritaine, A., Skryma, R., and Prevarskaya, N. (2016). Role of TRP ion channels in cancer and tumorigenesis. Seminars in Immunopathology, Springer.","DOI":"10.1007\/s00281-015-0525-1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/nrc2374","article-title":"Ca2+ signalling checkpoints in cancer: Remodelling Ca2+ for cancer cell proliferation and survival","volume":"8","author":"Roderick","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1786","DOI":"10.1016\/j.bbamcr.2018.05.015","article-title":"Calcium signaling and the therapeutic targeting of cancer cells","volume":"1865","author":"Bong","year":"2018","journal-title":"Biochim. Et Biophys. Acta Mol. Cell Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1016\/j.bbamcr.2016.01.002","article-title":"ER functions of oncogenes and tumor suppressors: Modulators of intracellular Ca2+ signaling","volume":"1863","author":"Bittremieux","year":"2016","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1423-0127-20-23","article-title":"Remodeling of calcium signaling in tumor progression","volume":"20","author":"Chen","year":"2013","journal-title":"J. Biomed. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s13578-018-0236-0","article-title":"Calcium signaling: An underlying link between cardiac disease and carcinogenesis","volume":"8","author":"Xu","year":"2018","journal-title":"Cell Biosci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-018-0223-5","article-title":"A temporal examination of calcium signaling in cancer-from tumorigenesis, to immune evasion, and metastasis","volume":"8","author":"Xu","year":"2018","journal-title":"Cell Biosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1039\/C7ME00046D","article-title":"In vitro delivery of calcium ions by nanogated mesoporous silica nanoparticles to induce cancer cellular apoptosis","volume":"2","author":"Tarn","year":"2017","journal-title":"Mol. Syst. Des. Eng."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coph.2016.03.002","article-title":"Alterations of calcium homeostasis in cancer cells","volume":"29","author":"Marchi","year":"2016","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"31666","DOI":"10.1074\/jbc.R112.343061","article-title":"Calcium channels and pumps in cancer: Changes and consequences","volume":"287","author":"Monteith","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"20130097","DOI":"10.1098\/rstb.2013.0097","article-title":"Remodelling of Ca2+ transport in cancer: How it contributes to cancer hallmarks?","volume":"369","author":"Prevarskaya","year":"2014","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"a035204","DOI":"10.1101\/cshperspect.a035204","article-title":"The calcium-signaling toolkit in cancer: Remodeling and targeting","volume":"11","author":"Chalmers","year":"2019","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1038\/ncb3124","article-title":"Metabolic pathways promoting cancer cell survival and growth","volume":"17","author":"Boroughs","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.tibs.2016.03.006","article-title":"Onco-IP3Rs feed cancerous cravings for mitochondrial Ca2+","volume":"41","author":"Bultynck","year":"2016","journal-title":"Trends Biochem. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"72324","DOI":"10.18632\/oncotarget.20327","article-title":"Downregulation of type 3 inositol (1, 4, 5)-trisphosphate receptor decreases breast cancer cell migration through an oscillatory Ca2+ signal","volume":"8","author":"Mound","year":"2017","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/j.ceca.2010.09.005","article-title":"The type III inositol 1, 4, 5-trisphosphate receptor is associated with aggressiveness of colorectal carcinoma","volume":"48","author":"Shibao","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1002\/jcb.25891","article-title":"Inhibition of Inositol 1, 4, 5-Trisphosphate Receptor Induce Breast Cancer Cell Death Through Deregulated Autophagy and Cellular Bioenergetics","volume":"118","author":"Singh","year":"2017","journal-title":"J. Cell. Biochem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.1158\/0008-5472.CAN-09-2886","article-title":"Caffeine-mediated inhibition of calcium release channel inositol 1, 4, 5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival","volume":"70","author":"Kang","year":"2010","journal-title":"Cancer Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"a035063","DOI":"10.1101\/cshperspect.a035063","article-title":"Structure and function of IP3 receptors","volume":"11","author":"Prole","year":"2019","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.cophys.2020.07.011","article-title":"Recent advances in understanding IP3R function with focus on ER-mitochondrial Ca2+ transfers","volume":"17","author":"Loncke","year":"2020","journal-title":"Curr. Opin. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00424-010-0826-0","article-title":"Inositol trisphosphate receptor Ca2+ release channels in neurological diseases","volume":"460","author":"Foskett","year":"2010","journal-title":"Pfl\u00fcgers Arch. -Eur. J. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/342032a0","article-title":"Primary structure and functional expression of the inositol 1, 4, 5-trisphosphate-binding protein P 400","volume":"342","author":"Furuichi","year":"1989","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"12679","DOI":"10.1016\/S0021-9258(19)38397-8","article-title":"Structure and expression of the rat inositol 1, 4, 5-trisphosphate receptor","volume":"265","author":"Mignery","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.ceca.2014.08.002","article-title":"Toward a high-resolution structure of IP3R channel","volume":"56","author":"Serysheva","year":"2014","journal-title":"Cell Calcium"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1426","DOI":"10.1111\/j.1471-4159.2007.04825.x","article-title":"IP3 receptor\/Ca2+ channel: From discovery to new signaling concepts","volume":"102","author":"Mikoshiba","year":"2007","journal-title":"J. Neurochem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4661","DOI":"10.1073\/pnas.1701420114","article-title":"IP3-mediated gating mechanism of the IP3 receptor revealed by mutagenesis and X-ray crystallography","volume":"114","author":"Hamada","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21319","DOI":"10.1074\/jbc.C300148200","article-title":"Structure of the type 1 inositol 1, 4, 5-trisphosphate receptor revealed by electron cryomicroscopy","volume":"278","author":"Serysheva","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"16613","DOI":"10.1016\/S0021-9258(18)42047-9","article-title":"Molecular cloning and characterization of the inositol 1, 4, 5-trisphosphate receptor in Drosophila melanogaster","volume":"267","author":"Yoshikawa","year":"1992","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"16551","DOI":"10.1074\/jbc.M300646200","article-title":"Critical regions for activation gating of the inositol 1, 4, 5-trisphosphate receptor","volume":"278","author":"Uchida","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1038\/s41594-018-0089-6","article-title":"Structural basis for the regulation of inositol trisphosphate receptors by Ca2+ and IP3","volume":"25","author":"Paknejad","year":"2018","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1074\/jbc.RA119.011570","article-title":"Cryo-EM structure of human type-3 inositol triphosphate receptor reveals the presence of a self-binding peptide that acts as an antagonist","volume":"295","author":"Azumaya","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1016\/j.cell.2010.06.007","article-title":"Essential regulation of cell bioenergetics by constitutive InsP3 receptor Ca2+ transfer to mitochondria","volume":"142","author":"Miller","year":"2010","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2313","DOI":"10.1016\/j.celrep.2016.02.030","article-title":"Selective vulnerability of cancer cells by inhibition of Ca2+ transfer from endoplasmic reticulum to mitochondria","volume":"14","author":"McNeal","year":"2016","journal-title":"Cell Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1016\/j.biochi.2010.06.015","article-title":"On the catalytic role of the active site residue E121 of E. coli L-aspartate oxidase","volume":"92","author":"Tedeschi","year":"2010","journal-title":"Biochimie"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2687","DOI":"10.1021\/jm049113+","article-title":"Anchor\u2212grind: Filling the gap between standard 3d qsar and the grid-independent descriptors","volume":"48","author":"Fontaine","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"6970","DOI":"10.1021\/jm050529c","article-title":"MetaSite: Understanding metabolism in human cytochromes from the perspective of the chemist","volume":"48","author":"Cruciani","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"S29","DOI":"10.1016\/S0928-0987(00)00162-7","article-title":"VolSurf: A new tool for the pharmacokinetic optimization of lead compounds","volume":"11","author":"Cruciani","year":"2000","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"21136","DOI":"10.3390\/ijms151121136","article-title":"The eTOX data-sharing project to advance in silico drug-induced toxicity prediction","volume":"15","author":"Cases","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1021\/ci9003317","article-title":"High-throughput virtual screening of proteins using GRID molecular interaction fields","volume":"50","author":"Sciabola","year":"2010","journal-title":"J. Chem. Inf. Model."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"D1100","DOI":"10.1093\/nar\/gkr777","article-title":"ChEMBL: A large-scale bioactivity database for drug discovery","volume":"40","author":"Gaulton","year":"2012","journal-title":"Nucl. Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1991","DOI":"10.1021\/jm980733i","article-title":"Synthesis, Calcium Mobilizing, and Physicochemical Properties of d-c hiro-Inositol 1, 3, 4, 6-Tetrakisphosphate, a Novel and Potent Ligand at the d-m yo-Inositol 1, 4, 5-Trisphosphate Receptor","volume":"42","author":"Liu","year":"1999","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1021\/jm981113k","article-title":"Enzyme-assisted total synthesis of the optical antipodes d-myo-inositol 3, 4, 5-trisphosphate and d-myo-inositol 1, 5, 6-trisphosphate: Aspects of their structure\u2212activity relationship to biologically active inositol phosphates","volume":"42","author":"Adelt","year":"1999","journal-title":"J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1002\/ejoc.200200572","article-title":"Stereoselective Synthesis of myo-, neo-, L-chiro, D-chiro, allo-, scyllo-, and epi-Inositol Systems via Conduritols Prepared from p-Benzoquinone","volume":"2003","author":"Podeschwa","year":"2003","journal-title":"Eur. J. Org. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ta, T.A., Feng, W., Molinski, T.F., and Pessah, I.N. (2005). Hydroxylated xestospongins block IP3-induced Ca2+ release and sensitize Ca2+-induced Ca2+ release mediated by ryanodine receptors. Mol. Pharmacol.","DOI":"10.1124\/mol.105.019125"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2051","DOI":"10.1016\/j.febslet.2005.02.053","article-title":"Xestospongin B, a competitive inhibitor of IP3-mediated Ca2+ signalling in cultured rat myotubes, isolated myonuclei, and neuroblastoma (NG108-15) cells","volume":"579","author":"Mattei","year":"2005","journal-title":"FEBS Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/S0896-6273(00)80384-0","article-title":"Xestospongins: Potent membrane permeable blockers of the inositol 1, 4, 5-trisphosphate receptor","volume":"19","author":"Gafni","year":"1997","journal-title":"Neuron"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1166\/msr.2012.1016","article-title":"Multivalent benzene polyphosphate derivatives are non-Ca2+-mobilizing Ins (1, 4, 5) P3 receptor antagonists","volume":"1","author":"Mills","year":"2012","journal-title":"Messenger"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1038\/nrd2445","article-title":"The influence of drug-like concepts on decision-making in medicinal chemistry","volume":"6","author":"Leeson","year":"2007","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"4406","DOI":"10.1016\/j.bmcl.2009.05.062","article-title":"Rapid assessment of a novel series of selective CB 2 agonists using parallel synthesis protocols: A lipophilic efficiency (LipE) analysis","volume":"19","author":"Ryckmans","year":"2009","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"3261","DOI":"10.1021\/jm201705f","article-title":"Structure\u2013activity relationships, ligand efficiency, and lipophilic efficiency profiles of benzophenone-type inhibitors of the multidrug transporter P-glycoprotein","volume":"55","author":"Jabeen","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"113","DOI":"10.4155\/fmc.12.208","article-title":"Lipophilic efficiency: The most important efficiency metric in medicinal chemistry","volume":"5","author":"Hoffman","year":"2013","journal-title":"Future Med. Chem."},{"key":"ref_52","first-page":"261","article-title":"Similarity of radial distribution function\u2019s intervals","volume":"56","author":"Podlipnik","year":"2006","journal-title":"Match-Commun. Math. Comput. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1023\/A:1008194019144","article-title":"Computational methods for the structural alignment of molecules","volume":"14","author":"Lemmen","year":"2000","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1002\/9781119161110.ch20","article-title":"3D pharmacophore modeling techniques in computer-aided molecular design using LigandScout","volume":"281","author":"Seidel","year":"2017","journal-title":"Tutor. Chemoinform"},{"key":"ref_55","unstructured":"G\u00fcner, O.F. (2000). Pharmacophore Perception, Development, and Use in Drug Design, Internat University Line."},{"key":"ref_56","unstructured":"Mannhold, R., Kubinyi, H., and Folkers, G. (2006). Pharmacophores and Pharmacophore Searches, John Wiley & Sons."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1111\/j.1476-5381.1995.tb14931.x","article-title":"Inhibition of calcium release from the sarcoplasmic reticulum of rabbit aorta by hydralazine","volume":"114","author":"Gurney","year":"1995","journal-title":"Br. J. Pharmacol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1016\/j.neulet.2008.02.076","article-title":"Levetiracetam inhibits both ryanodine and IP3 receptor activated calcium induced calcium release in hippocampal neurons in culture","volume":"436","author":"Nagarkatti","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1016\/0006-2952(87)90307-8","article-title":"Inhibitors of inositol trisphosphate-induced Ca2+ release from isolated platelet membrane vesicles","volume":"36","author":"Seiler","year":"1987","journal-title":"Biochem. Pharmacol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1107\/S0108768102003890","article-title":"The Cambridge Structural Database: A quarter of a million crystal structures and rising","volume":"58","author":"Allen","year":"2002","journal-title":"Acta Crystallogr. Sect. B Struct. Sci."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1021\/ci00021a032","article-title":"National Cancer Institute drug information system 3D database","volume":"34","author":"Milne","year":"1994","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1021\/ci010056s","article-title":"Enhanced CACTVS browser of the Open NCI Database","volume":"42","author":"Ihlenfeldt","year":"2002","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1021\/ci3001277","article-title":"ZINC: A free tool to discover chemistry for biology","volume":"52","author":"Irwin","year":"2012","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"E101","DOI":"10.1208\/aapsj080112","article-title":"Cytochrome P450s and other enzymes in drug metabolism and toxicity","volume":"8","author":"Guengerich","year":"2006","journal-title":"AAPS J."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1007\/s10822-011-9440-2","article-title":"Online chemical modeling environment (OCHEM): Web platform for data storage, model development and publishing of chemical information","volume":"25","author":"Sushko","year":"2011","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_66","unstructured":"(2021, September 17). Molecular Operating Environment (MOE). Chemical Computing Group Inc., 2019.01., 1010 Sherbooke St. West, Suite #910, Montreal, QC, Canada, 2015, Volume 49. Available online: www.chemcomp.com\/index.htm."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"4371","DOI":"10.1021\/ja00194a034","article-title":"A new approach to probing conformational space with molecular mechanics: Random incremental pulse search","volume":"111","author":"Ferguson","year":"1989","journal-title":"J. Am. Chem. Soc."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1093\/toxsci\/kfm026","article-title":"Preclinical cardiovascular risk assessment in modern drug development","volume":"97","author":"Guth","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/S0008-6363(02)00846-5","article-title":"Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: Evidence for a provisional safety margin in drug development","volume":"58","author":"Redfern","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1035","DOI":"10.3389\/fphar.2018.01035","article-title":"Experimentally validated pharmacoinformatics approach to predict hERG inhibition potential of new chemical entities","volume":"9","author":"Munawar","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_71","first-page":"82","article-title":"Pymol: An open-source molecular graphics tool","volume":"40","author":"DeLano","year":"2002","journal-title":"CCP4 Newsl. Protein Crystallogr."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"18277","DOI":"10.1074\/jbc.271.30.18277","article-title":"Mutational analysis of the ligand binding site of the inositol 1, 4, 5-trisphosphate receptor","volume":"271","author":"Yoshikawa","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.bbamcr.2004.09.016","article-title":"Structural insights into the regulatory mechanism of IP3 receptor","volume":"174","author":"Bosanac","year":"2004","journal-title":"Biochim. Biophys. Acta Mol. Cell Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Ismatullah, H., Jabeen, I., and Saeed, M.T. (2021). Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer. Genes, 12.","DOI":"10.3390\/genes12010034"},{"key":"ref_75","unstructured":"(2009). Pentacle Version 1.0.7, Molecular Discovery Ltd.. Available online: https:\/\/www.moldiscovery.com."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1002\/qsar.19930120103","article-title":"Generating optimal linear PLS estimations (GOLPE): An advanced chemometric tool for handling 3D-QSAR problems","volume":"12","author":"Baroni","year":"1993","journal-title":"Quant. Struct. Act. Relatsh."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"13","DOI":"10.2174\/1570163053175439","article-title":"Autocorrelation of molecular electrostatic potential surface properties combined with partial least squares analysis as alternative attractive tool to generate ligand-based 3D-QSARs","volume":"2","author":"Moro","year":"2005","journal-title":"Curr. Drug Discov. Technol."},{"key":"ref_78","first-page":"111","article-title":"Leave-one-out error and stability of learning algorithms with applications","volume":"190","author":"Elisseeff","year":"2003","journal-title":"NATO Sci. Ser. Sub Ser. Iii Comput. Syst. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1021\/ci025626i","article-title":"Assessing model fit by cross-validation","volume":"43","author":"Hawkins","year":"2003","journal-title":"J. Chem. Inf. Comput. Sci."},{"key":"ref_80","first-page":"511","article-title":"Validation of QSAR models-strategies and importance","volume":"3","author":"Veerasamy","year":"2011","journal-title":"Int. J. Drug Des. Discov."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1021\/ci200520g","article-title":"Comparative studies on some metrics for external validation of QSPR models","volume":"52","author":"Roy","year":"2012","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1002\/qsar.200710043","article-title":"On some aspects of variable selection for partial least squares regression models","volume":"27","author":"Roy","year":"2008","journal-title":"QSAR Comb. Sci."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1660","DOI":"10.3390\/molecules14051660","article-title":"On two novel parameters for validation of predictive QSAR models","volume":"14","author":"Pratim","year":"2009","journal-title":"Molecules"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.chemolab.2015.04.013","article-title":"On a simple approach for determining applicability domain of QSAR models","volume":"145","author":"Roy","year":"2015","journal-title":"Chemom. Intell. Lab. Syst."},{"key":"ref_85","unstructured":"Snedecor, G., and Cochran, W. (1967). Statistical Methods, Oxford and IBH Publishing Co. [6th ed.]."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrc.2017.18","article-title":"The calcium\u2013cancer signalling nexus","volume":"17","author":"Monteith","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1126\/scisignal.aay1212","article-title":"Cancer cells with defective oxidative phosphorylation require endoplasmic reticulum\u2013to\u2013mitochondria Ca2+ transfer for survival","volume":"13","author":"Cardenas","year":"2020","journal-title":"Sci. Signal."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1038\/s41422-018-0108-5","article-title":"Cryo-EM reveals ligand induced allostery underlying InsP 3 R channel gating","volume":"28","author":"Fan","year":"2018","journal-title":"Cell Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"9234","DOI":"10.1021\/bi990114r","article-title":"Molecular recognition of adenophostin, a very potent Ca2+ inducer, at the D-myo-inositol 1, 4, 5-trisphosphate receptor","volume":"38","author":"Hotoda","year":"1999","journal-title":"Biochemistry"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1038\/nature01268","article-title":"Structure of the inositol 1, 4, 5-trisphosphate receptor binding core in complex with its ligand","volume":"420","author":"Bosanac","year":"2002","journal-title":"Nature"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.molcel.2004.11.047","article-title":"Crystal structure of the ligand binding suppressor domain of type 1 inositol 1, 4, 5-trisphosphate receptor","volume":"17","author":"Bosanac","year":"2005","journal-title":"Mol. Cell"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1152\/physrev.00035.2006","article-title":"Inositol trisphosphate receptor Ca2+ release channels","volume":"87","author":"Foskett","year":"2007","journal-title":"Physiol. Rev."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"12780","DOI":"10.1021\/bi971397v","article-title":"Disaccharide polyphosphates based upon adenophostin A activate hepatic D-myo-inositol 1, 4, 5-trisphosphate receptors","volume":"36","author":"Marchant","year":"1997","journal-title":"Biochemistry"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1006\/mcbr.2000.0208","article-title":"Association of the inositol (1, 4, 5)-trisphosphate receptor ligand binding site with phosphatidylinositol (4, 5)-bisphosphate and adenophostin A","volume":"3","author":"Glouchankova","year":"2000","journal-title":"Mol. Cell Biol. Res. Commun."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"8106","DOI":"10.1074\/jbc.M108337200","article-title":"A novel recombinant hyperaffinity inositol 1, 4, 5-trisphosphate (IP3) absorbent traps IP3, resulting in specific inhibition of IP3-mediated calcium signaling","volume":"277","author":"Uchiyama","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"36092","DOI":"10.1074\/jbc.M110.140160","article-title":"Structural studies of inositol 1, 4, 5-trisphosphate receptor coupling ligand binding to channel gating","volume":"285","author":"Chan","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1038\/nsmb.2112","article-title":"Apo and InsP 3-bound crystal structures of the ligand-binding domain of an InsP 3 receptor","volume":"18","author":"Lin","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"5039","DOI":"10.1021\/jm0704651","article-title":"Influence of conformation on GRIND-based three-dimensional quantitative structure\u2212activity relationship (3D-QSAR)","volume":"50","author":"Caron","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"5912","DOI":"10.1021\/jm050362n","article-title":"A critical assessment of docking programs and scoring functions","volume":"49","author":"Warren","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1002\/qsar.200390007","article-title":"The importance of being earnest: Validation is the absolute essential for successful application and interpretation of QSPR models","volume":"22","author":"Tropsha","year":"2003","journal-title":"QSAR Comb. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"13071","DOI":"10.1016\/S0021-9258(18)69272-5","article-title":"Effects of sulfhydryl reagents and other inhibitors on Ca2+ transport and inositol trisphosphate-induced Ca2+ release from human platelet membranes","volume":"261","author":"Adunyah","year":"1986","journal-title":"J. Biol. Chem."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1016\/0006-291X(87)90492-X","article-title":"Heparin inhibits inositol trisphosphate-induced calcium release from permeabilized rat liver cells","volume":"149","author":"Hill","year":"1987","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/0143-4160(91)90042-D","article-title":"Decavanadate displaces inositol 1, 4, 5-trisphosphate (IP3) from its receptor and inhibits IP3 induced Ca2+ release in permeabilized pancreatic acinar cells","volume":"12","author":"Wahl","year":"1991","journal-title":"Cell Calcium"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/0922-4106(93)90145-Y","article-title":"Interaction of benzene 1, 2, 4-trisphosphate with inositol 1, 4, 5-trisphosphate receptor and metabolizing enzymes","volume":"244","author":"Poitras","year":"1993","journal-title":"Eur. J. Pharmacol. Mol. Pharmacol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/0006-3223(95)00657-5","article-title":"Antipsychotic drugs block IP3-dependent Ca2+-release from rat brain microsomes","volume":"40","author":"Sczekan","year":"1996","journal-title":"Biol. Psychiatry"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/0006-2952(65)90102-4","article-title":"A sensitive and specific fluorescence assay for tissue serotonin","volume":"14","author":"Snyder","year":"1965","journal-title":"Biochem. Pharmacol."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"11819","DOI":"10.1021\/bi00115a012","article-title":"Fluorescence assay for phospholipid membrane asymmetry","volume":"30","author":"McIntyre","year":"1991","journal-title":"Biochemistry"},{"key":"ref_108","doi-asserted-by":"crossref","unstructured":"Csizmadia, P. (1999, January 1\u201330). MarvinSketch and MarvinView: Molecule Applets for the World Wide Web. Proceedings of the The 3rd International Electronic Conference on Synthetic Organic Chemistry, Budapest, Hungary.","DOI":"10.3390\/ecsoc-3-01775"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1002\/(SICI)1096-987X(199604)17:5\/6<520::AID-JCC2>3.0.CO;2-W","article-title":"Merck molecular force field. II. MMFF94 van der Waals and electrostatic parameters for intermolecular interactions","volume":"17","author":"Halgren","year":"1996","journal-title":"J. Comput. Chem."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"580","DOI":"10.1002\/wcms.33","article-title":"Diversity selection algorithms","volume":"1","author":"Gillet","year":"2011","journal-title":"Wiley Interdiscip. Rev. Comput. Mol. Sci."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1219","DOI":"10.1021\/jm960352+","article-title":"Selecting optimally diverse compounds from structure databases: A validation study of two-dimensional and three-dimensional molecular descriptors","volume":"40","author":"Matter","year":"1997","journal-title":"J. Med. Chem."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1023\/B:MODI.0000047503.82461.e8","article-title":"Impact of different software implementations on the performance of the Maxmin method for diverse subset selection","volume":"8","author":"Schmuker","year":"2004","journal-title":"Mol. Divers."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2322","DOI":"10.1007\/s00044-017-1933-7","article-title":"Molecular docking simulations and GRID-independent molecular descriptor (GRIND) analysis to probe stereoselective interactions of CYP3A4 inhibitors","volume":"26","author":"Mukhtar","year":"2017","journal-title":"Med. Chem. Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"e6283","DOI":"10.7717\/peerj.6283","article-title":"GRID-independent molecular descriptor analysis and molecular docking studies to mimic the binding hypothesis of \u03b3-aminobutyric acid transporter 1 (GAT1) inhibitors","volume":"7","author":"Zafar","year":"2019","journal-title":"PeerJ"},{"key":"ref_115","doi-asserted-by":"crossref","unstructured":"Munawar, S., Vandenberg, J.I., and Jabeen, I. (2019). Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143385"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and testing of a general amber force field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"4023","DOI":"10.1021\/acs.jpcb.7b02320","article-title":"Building a more predictive protein force field: A systematic and reproducible route to AMBER-FB15","volume":"121","author":"Wang","year":"2017","journal-title":"J. Phys. Chem. B"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"6507","DOI":"10.1021\/jm070593p","article-title":"A flexible approach to induced fit docking","volume":"50","author":"Nabuurs","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0165-6147(98)01260-7","article-title":"New developments in the molecular pharmacology of the myo-inositol 1, 4, 5-trisphosphate receptor","volume":"19","author":"Wilcox","year":"1998","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1038\/nrd2438","article-title":"Carrier-mediated cellular uptake of pharmaceutical drugs: An exception or the rule?","volume":"7","author":"Dobson","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1008762321231","article-title":"Role of hydrophobic effects in mechanistic QSAR","volume":"17","author":"Leo","year":"1999","journal-title":"Perspect. Drug Discov. Des."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1517\/17460441.2012.714363","article-title":"The influence of lipophilicity in drug discovery and design","volume":"7","author":"Arnott","year":"2012","journal-title":"Expert Opin. Drug Discov."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nrd2796","article-title":"The influence of lead discovery strategies on the properties of drug candidates","volume":"8","author":"Makara","year":"2009","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10822-011-9435-z","article-title":"Assessing the lipophilicity of fragments and early hits","volume":"25","author":"Mortenson","year":"2011","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1038\/nrd4163","article-title":"The role of ligand efficiency metrics in drug discovery","volume":"13","author":"Hopkins","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1007\/s10822-006-9078-7","article-title":"Efficient overlay of small organic molecules using 3D pharmacophores","volume":"20","author":"Wolber","year":"2006","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1021\/ci049885e","article-title":"LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters","volume":"45","author":"Wolber","year":"2005","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3389\/fchem.2018.00229","article-title":"Conformational Sampling of Small Molecules With iCon: Performance Assessment in Comparison With OMEGA","volume":"6","author":"Poli","year":"2018","journal-title":"Front. Chem."},{"key":"ref_129","first-page":"1141","article-title":"Molecular similarity","volume":"24","author":"Hodgkin","year":"1988","journal-title":"Chem. Ber."},{"key":"ref_130","unstructured":"Dur\u00e1n, \u00c1., and Pastor, M. (2011). An Advanced Tool for Computing and Handling GRid-INdependent. Descriptors, User Manual Version."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/0898-5529(90)90156-3","article-title":"Automatic generation of 3D-atomic coordinates for organic molecules","volume":"3","author":"Gasteiger","year":"1990","journal-title":"Tetrahedron Comput. Methodol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/wcms.1150","article-title":"Molecular interaction fields in drug discovery: Recent advances and future perspectives. Wiley Interdisciplinary Reviews","volume":"3","author":"Artese","year":"2013","journal-title":"Comput. Mol. Sci."},{"key":"ref_133","unstructured":"Mannhold, R., Kubinyi, H., and Folkers, G. (2006). Molecular Interaction Fields: Applications in Drug Discovery and ADME Prediction, John Wiley & Sons."},{"key":"ref_134","first-page":"595","article-title":"Calculation of the Lennard-Jones nm potential energy parameters for metals. Physica Status Solidi","volume":"78","author":"Shu","year":"1983","journal-title":"A Appl. Res."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.jms.2010.07.003","article-title":"An extended Lennard-Jones potential energy function for diatomic molecules: Application to ground electronic states","volume":"263","author":"Hajigeorgiou","year":"2010","journal-title":"J. Mol. Spectrosc."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1813","DOI":"10.1021\/ci800037t","article-title":"Development and validation of AMANDA, a new algorithm for selecting highly relevant regions in molecular interaction fields","volume":"48","author":"Duran","year":"2008","journal-title":"J. Chem. Inf. Modeling"},{"key":"ref_137","unstructured":"Dur\u00e1n, A.\u00c1. (2010). Development of high-performance algorithms for a new generation of versatile molecular descriptors. The Pentacle Software, Universitat Pompeu Fabra. Available online: http:\/\/hdl.handle.net\/10803\/7201."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12993\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:38:10Z","timestamp":1760168290000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/23\/12993"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,30]]},"references-count":137,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["ijms222312993"],"URL":"https:\/\/doi.org\/10.3390\/ijms222312993","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,30]]}}}