{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T19:38:12Z","timestamp":1790797092848,"version":"4.1.0"},"reference-count":63,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T00:00:00Z","timestamp":1596499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"DOI":"10.3389\/fendo.2020.00517","type":"journal-article","created":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T04:46:15Z","timestamp":1596516375000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":32,"title":["Computational Approaches for the Discovery of GPER Targeting Compounds"],"prefix":"10.3389","volume":"11","author":[{"given":"Fedora","family":"Grande","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria A.","family":"Occhiuzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosamaria","family":"Lappano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Cirillo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Guzzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Garofalo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Jacquot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Maggiolini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Rizzuti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2020,8,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.mce.2005.03.007","article-title":"The role of DNA response elements as allosteric modulators of steroid receptor function","volume":"236","author":"Geserick","year":"2005","journal-title":"Mol Cell Endocrinol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.jsbmb.2017.03.021","article-title":"Twenty years of the G protein-coupled estrogen receptor GPER: historical and personal perspectives","volume":"176","author":"Barton","year":"2018","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1038\/emboj.2008.304","article-title":"Estrogenic GPR30 signalling induces proliferation and migration of breast cancer cells through CTGF","volume":"28","author":"Pandey","year":"2009","journal-title":"EMBO J."},{"key":"B4","doi-asserted-by":"publisher","first-page":"4053","DOI":"10.1158\/0008-5472.CAN-13-3590","article-title":"GPER mediates activation of HIF1\u03b1\/VEGF signaling by estrogens","volume":"74","author":"De Francesco","year":"2014","journal-title":"Cancer Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"24354","DOI":"10.1038\/srep24354","article-title":"GPER signalling in both cancer-associated fibroblasts and breast cancer cells mediates a feedforward IL1\u03b2\/IL1R1 response","volume":"6","author":"De Marco","year":"2016","journal-title":"Sci Rep."},{"key":"B6","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s13046-019-1056-8","article-title":"Focal adhesion kinase (FAK) activation by estrogens involves GPER in triple-negative breast cancer cells","volume":"38","author":"Rigiracciolo","year":"2019","journal-title":"J Exp Clin Cancer Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"66","DOI":"10.3389\/fendo.2014.00066","article-title":"GPER function in breast cancer: an overview","volume":"5","author":"Lappano","year":"2014","journal-title":"Front Endocrinol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"223","DOI":"10.3390\/cells8030223","article-title":"GPER mediates a feedforward FGF2\/FGFR1 paracrine activation coupling CAFs to cancer cells toward breast tumor progression","volume":"8","author":"Santolla","year":"2019","journal-title":"Cells."},{"key":"B9","doi-asserted-by":"publisher","first-page":"106608","DOI":"10.18632\/oncotarget.22541","article-title":"GPER is involved in the regulation of the estrogen-metabolizing CYP1B1 enzyme in breast cancer","volume":"8","author":"Cirillo","year":"2017","journal-title":"Oncotarget."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1649","DOI":"10.1210\/mend.14.10.0532","article-title":"Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF","volume":"14","author":"Filardo","year":"2000","journal-title":"Mol Endocrinol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1158\/1541-7786.MCR-14-0128-T","article-title":"G protein-coupled estrogen receptor regulates mammary tumorigenesis and metastasis","volume":"12","author":"Marjon","year":"2014","journal-title":"Mol Cancer Res."},{"key":"B12","doi-asserted-by":"publisher","first-page":"6359","DOI":"10.1158\/1078-0432.CCR-06-0860","article-title":"Distribution of GPR30, a seven membrane-spanning estrogen receptor, in primary breast cancer and its association with clinicopathologic determinants of tumor progression","volume":"12","author":"Filardo","year":"2006","journal-title":"Clin Cancer Res."},{"key":"B13","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1016\/j.ajog.2007.01.004","article-title":"GPR30: a novel indicator of poor survival for endometrial carcinoma","volume":"196","author":"Smith","year":"2007","journal-title":"Am J Obstet Gynecol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/j.ygyno.2009.05.015","article-title":"GPR30 predicts poor survival for ovarian cancer","volume":"114","author":"Smith","year":"2009","journal-title":"Gynecol Oncol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"622","DOI":"10.3390\/cells9030622","article-title":"The G protein-coupled estrogen receptor (GPER) expression correlates with pro-metastatic pathways in ER-negative breast cancer: a bioinformatics analysis","volume":"9","author":"Talia","year":"2020","journal-title":"Cells."},{"key":"B16","doi-asserted-by":"publisher","first-page":"25946","DOI":"10.18632\/oncotarget.25408","article-title":"Low expression of G protein-coupled oestrogen receptor 1 (GPER) is associated with adverse survival of breast cancer patients","volume":"9","author":"Martin","year":"2018","journal-title":"Oncotarget."},{"key":"B17","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1210\/en.2004-1064","article-title":"Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells","volume":"146","author":"Thomas","year":"2005","journal-title":"Endocrinology."},{"key":"B18","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.mce.2010.02.006","article-title":"Estriol acts as a GPR30 antagonist in estrogen receptor-negative breast cancer cells","volume":"320","author":"Lappano","year":"2010","journal-title":"Mol Cell Endocrinol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nchembio775","article-title":"Virtual and biomolecular screening converge on a selective agonist for GPR30","volume":"2","author":"Bologa","year":"2006","journal-title":"Nat Chem Biol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nchembio.168","article-title":"In vivo effects of a GPR30 antagonist","volume":"5","author":"Dennis","year":"2009","journal-title":"Nat Chem Biol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jsbmb.2011.07.002","article-title":"Identification of a GPER\/GPR30 antagonist with improved estrogen receptor counterselectivity","volume":"127","author":"Dennis","year":"2011","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"531","DOI":"10.2174\/156800912800673284","article-title":"Two novel GPER agonists induce gene expression changes and growth effects in cancer cells","volume":"12","author":"Lappano","year":"2012","journal-title":"Curr Cancer Drug Targets."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1035","DOI":"10.2174\/1568026615666150317221549","article-title":"(6-bromo-1,4-dimethyl-9H-carbazol-3-yl-methylene)-hydrazine (carbhydraz) acts as a GPER agonist in breast cancer cells","volume":"15","author":"Sinicropi","year":"2015","journal-title":"Curr Top Med Chem"},{"key":"B24","doi-asserted-by":"publisher","first-page":"437","DOI":"10.4155\/fmc.15.3","article-title":"Identification of two benzopyrroloxazines acting as selective GPER antagonists in breast cancer cells and cancer-associated fibroblasts","volume":"7","author":"Maggiolini","year":"2015","journal-title":"Future Med Chem."},{"key":"B25","doi-asserted-by":"publisher","first-page":"590","DOI":"10.3390\/cells8060590","article-title":"The peptide ER\u03b117p is a GPER inverse agonist that exerts antiproliferative effects in breast cancer cells","volume":"8","author":"Lappano","year":"2019","journal-title":"Cells."},{"key":"B26","doi-asserted-by":"publisher","first-page":"3004","DOI":"10.1093\/bioinformatics\/btq563","article-title":"GPCRRD: G protein-coupled receptor spatial restraint database for 3D structure modeling and function annotation","volume":"26","author":"Zhang","year":"2010","journal-title":"Bioinformatics."},{"key":"B27","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.mce.2009.03.026","article-title":"Mechanisms of estrogen signaling and gene expression via GPR30","volume":"308","author":"Prossnitz","year":"2009","journal-title":"Mol Cell Endocrinol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1080\/07391102.2003.10506892","article-title":"Plausible interaction of an alpha-fetoprotein cyclopeptide with the G-protein-coupled receptor model GPR30: docking study by molecular dynamics simulated annealing","volume":"20","author":"Hamza","year":"2003","journal-title":"J Biomol Struct Dyn."},{"key":"B29","doi-asserted-by":"publisher","first-page":"R12","DOI":"10.1186\/bcr3096","article-title":"MIBE acts as antagonist ligand of both estrogen receptor \u03b1 and GPER in breast cancer cells","volume":"14","author":"Lappano","year":"2012","journal-title":"Breast Cancer Res."},{"key":"B30","doi-asserted-by":"publisher","first-page":"6199","DOI":"10.2174\/0929867311209066199","article-title":"Recent advances in the rationale design of GPER ligands","volume":"19","author":"Rosano","year":"2012","journal-title":"Curr Med Chem."},{"key":"B31","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1208\/s12248-015-9844-3","article-title":"Macromolecular modelling and docking simulations for the discovery of selective GPER ligands","volume":"18","author":"Rosano","year":"2016","journal-title":"AAPS J."},{"key":"B32","doi-asserted-by":"publisher","first-page":"571","DOI":"10.1016\/j.jmb.2004.07.044","article-title":"The retinal conformation and its environment in rhodopsin in light of a new 2.2 \u00c5 crystal structure","volume":"342","author":"Okada","year":"2004","journal-title":"J Mol Biol."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1126\/science.1150577","article-title":"High-resolution crystal structure of an engineered human \u03b22-adrenergic G protein-coupled receptor","volume":"318","author":"Cherezov","year":"2007","journal-title":"Science."},{"key":"B34","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/nature10361","article-title":"Crystal structure of the \u03b22 adrenergic receptor-Gs protein complex","volume":"477","author":"Rasmussen","year":"2011","journal-title":"Nature."},{"key":"B35","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1002\/minf.201200136","article-title":"G Protein-coupled estrogen receptor (GPER) agonist dual binding mode analyses toward understanding of its activation mechanism: a comparative homology modeling approach","volume":"32","author":"Arnatt","year":"2013","journal-title":"Mol Inform."},{"key":"B36","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1002\/minf.201501024","article-title":"Homology modeling, validation and dynamics of the G protein-coupled estrogen receptor 1 (GPER-1)","volume":"35","author":"Bruno","year":"2016","journal-title":"Mol Inform."},{"key":"B37","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1126\/science.1194396","article-title":"Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists","volume":"330","author":"Wu","year":"2010","journal-title":"Science."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2161","DOI":"10.1080\/07391102.2014.994102","article-title":"Deciphering the GPER\/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations","volume":"33","author":"M\u00e9ndez-Luna","year":"2015","journal-title":"J Biomol Struct Dyn."},{"key":"B39","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1016\/j.jsbmb.2016.01.001","article-title":"Understanding the molecular basis of agonist\/antagonist mechanism of GPER1\/GPR30 through structural and energetic analyses","volume":"158","author":"M\u00e9ndez-Luna","year":"2016","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1538","DOI":"10.1016\/j.str.2015.06.007","article-title":"GPCR-I-TASSER: a hybrid approach to G protein-coupled receptor structure modeling and the application to the human genome","volume":"23","author":"Zhang","year":"2015","journal-title":"Structure."},{"key":"B41","doi-asserted-by":"publisher","first-page":"725","DOI":"10.1038\/nprot.2010.5","article-title":"I-TASSER: a unified platform for automated protein structure and function prediction","volume":"5","author":"Roy","year":"2010","journal-title":"Nat Protoc."},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1101\/461681","article-title":"Locating ligand binding sites in G-protein coupled receptors using combined information from docking and sequence conservation","author":"Vidad","year":"2019","journal-title":"bioRxiv [Preprint]"},{"key":"B43","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1186\/s13046-019-1337-2","article-title":"AHR and GPER mediate the stimulatory effects induced by 3-methylcholanthrene in breast cancer cells and cancer-associated fibroblasts (CAFs)","volume":"38","author":"Cirillo","year":"2019","journal-title":"J Exp Clin Cancer Res."},{"key":"B44","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.jsbmb.2012.12.014","article-title":"The structural biology of oestrogen metabolism","volume":"137","author":"Thomas","year":"2013","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"478","DOI":"10.1002\/mnfr.201300323","article-title":"Oleuropein and hydroxytyrosol activate GPER\/ GPR30-dependent pathways leading to apoptosis of ER-negative SKBR3 breast cancer cells","volume":"58","author":"Chimento","year":"2014","journal-title":"Mol Nutr Food Res."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1466","DOI":"10.1016\/j.cellsig.2014.03.011","article-title":"Niacin activates the G protein estrogen receptor (GPER)-mediated signalling","volume":"26","author":"Santolla","year":"2014","journal-title":"Cell Signal."},{"key":"B47","doi-asserted-by":"publisher","first-page":"10437","DOI":"10.1039\/C5OB01827G","article-title":"Bodipy as a luminescent probe for detection of the G protein estrogen receptor (GPER)","volume":"13","author":"Papalia","year":"2015","journal-title":"Org Biomol Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1016\/j.phrs.2015.08.014","article-title":"The effects of (\u2013)-epicatechin on endothelial cells involve the G protein-coupled estrogen receptor (GPER)","volume":"100","author":"Moreno-Ulloa","year":"2015","journal-title":"Pharmacol Res."},{"key":"B49","doi-asserted-by":"publisher","first-page":"4252","DOI":"10.1210\/endo.139.10.6216","article-title":"Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor \u03b2","volume":"139","author":"Kuiper","year":"1998","journal-title":"Endocrinology."},{"key":"B50","doi-asserted-by":"publisher","first-page":"894","DOI":"10.3390\/molecules23040894","article-title":"Identification by molecular docking of homoisoflavones from Leopoldia comosa as ligands of estrogen receptors","volume":"23","author":"Grande","year":"2018","journal-title":"Molecules."},{"key":"B51","doi-asserted-by":"publisher","first-page":"7450","DOI":"10.1038\/s41598-019-43768-5","article-title":"Determination and analysis of agonist and antagonist potential of naturally occurring flavonoids for estrogen receptor (ER\u03b1) by various parameters and molecular modelling approach","volume":"9","author":"Puranik","year":"2019","journal-title":"Sci Rep."},{"key":"B52","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.bmcl.2018.01.025","article-title":"Synthesis of novel (\u2013)-epicatechin derivatives as potential endothelial GPER agonists: evaluation of biological effects","volume":"28","author":"Sarmiento","year":"2018","journal-title":"Bioorg Med Chem Lett."},{"key":"B53","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1016\/j.jsbmb.2019.03.006","article-title":"Structural and energetic basis for novel epicatechin derivatives acting as GPER agonists through the MMGBSA method","volume":"189","author":"Bello","year":"2019","journal-title":"J Steroid Biochem Mol Biol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1629","DOI":"10.2174\/1871520618666180510121431","article-title":"Selection of a GPER1 ligand via ligand-based virtual screening coupled to molecular dynamics simulations and its anti-proliferative effects on breast cancer cells","volume":"18","author":"Mart\u00ednez-Mu\u00f1oz","year":"2018","journal-title":"Anticancer Agents Med Chem."},{"key":"B55","doi-asserted-by":"publisher","first-page":"760","DOI":"10.2174\/1871520618666181119094144","article-title":"Synthesis and in vitro evaluation of tetrahydroquinoline derivatives as antiproliferative compounds of breast cancer via targeting the GPER","volume":"19","author":"Zacar\u00edas-Lara","year":"2019","journal-title":"Anticancer Agents Med Chem."},{"key":"B56","doi-asserted-by":"publisher","first-page":"641","DOI":"10.3389\/fgene.2018.00641","article-title":"Secoisolariciresinol diglucoside of flaxseed and its metabolites: Biosynthesis and potential for nutraceuticals","volume":"9","author":"Kezimana","year":"2018","journal-title":"Front Genet."},{"key":"B57","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1139\/apnm-2016-0332","article-title":"The treatment effects of flaxseed-derived secoisolariciresinol diglycoside and its metabolite enterolactone on benign prostatic hyperplasia involve the G protein-coupled estrogen receptor 1","volume":"41","author":"Ren","year":"2016","journal-title":"Appl Physiol Nutr Metab."},{"key":"B58","doi-asserted-by":"publisher","first-page":"10470","DOI":"10.18632\/oncotarget.14433","article-title":"Baicalein has protective effects on the 17\u03b2-estradiol-induced transformation of breast epithelial cells","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget."},{"key":"B59","doi-asserted-by":"publisher","first-page":"11423","DOI":"10.1021\/acs.est.7b03336","article-title":"Bisphenol AF and bisphenol B exert higher estrogenic effects than bisphenol A via G protein-coupled estrogen receptor pathway","volume":"51","author":"Cao","year":"2017","journal-title":"Environ Sci Technol."},{"key":"B60","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.maturitas.2010.10.003","article-title":"Lack of sufficient information on the specificity and selectivity of commercial phytoestrogens preparations for therapeutic purposes","volume":"68","author":"Leclercq","year":"2011","journal-title":"Maturitas."},{"key":"B61","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1002\/cmdc.201700145","article-title":"Identification of breast cancer inhibitors specific for G protein-coupled estrogen receptor (GPER)-expressing cells","volume":"12","author":"Aiello","year":"2017","journal-title":"ChemMedChem."},{"key":"B62","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3390\/cells9020447","article-title":"Interaction of the anti-proliferative GPER inverse agonist ER\u03b117p with the breast cancer cell plasma membrane: from biophysics to biology","volume":"9","author":"Trichet","year":"2020","journal-title":"Cells."},{"key":"B63","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.molonc.2010.11.001","article-title":"The estrogen receptor \u03b1-derived peptide ER\u03b117p (P295-T311) exerts pro-apoptotic actions in breast cancer cells in vitro and in vivo, independently from their ER\u03b1 status","volume":"5","author":"Pelekanou","year":"2011","journal-title":"Mol Oncol."}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fendo.2020.00517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,8,4]],"date-time":"2020-08-04T04:46:18Z","timestamp":1596516378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/article\/10.3389\/fendo.2020.00517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,8,4]]},"references-count":63,"alternative-id":["10.3389\/fendo.2020.00517"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2020.00517","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,8,4]]},"article-number":"517"}}