{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:40Z","timestamp":1785428260201,"version":"3.56.0"},"reference-count":35,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,26]],"date-time":"2026-07-26T00:00:00Z","timestamp":1785024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008402","name":"Chengdu University of Traditional Chinese Medicine","doi-asserted-by":"crossref","award":["030040043"],"award-info":[{"award-number":["030040043"]}],"id":[{"id":"10.13039\/501100008402","id-type":"DOI","asserted-by":"crossref"}]},{"award":["030040043"],"award-info":[{"award-number":["030040043"]}],"id":[{"id":"https:\/\/ror.org\/00pcrz470","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100018542","name":"Natural Science Foundation of Sichuan","doi-asserted-by":"crossref","award":["2025NSFJQ0032"],"award-info":[{"award-number":["2025NSFJQ0032"]}],"id":[{"id":"10.13039\/501100018542","id-type":"DOI","asserted-by":"crossref"}]},{"name":"State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine","award":["CBCM2024107"],"award-info":[{"award-number":["CBCM2024107"]}]},{"name":"Sichuan Provincial Administration of Traditional Chinese Medicine Special Fund"},{"id":[{"id":"https:\/\/ror.org\/03x55t826","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Background: The C-X-C chemokine receptor type 7 (CXCR7), also known as atypical chemokine receptor 3 (ACKR3), primarily signals through \u03b2-arrestin and plays a pivotal role in tumor progression, inflammation, and neurodegenerative diseases. CXCR7 antagonists block chemokine binding and dampen \u03b2-arrestin signaling. Accordingly, identification of such antagonists is highly desirable for therapeutic development against CXCR7 driven pathologies. Methods: Through microscale thermophoresis (MST) screening of a Food and Drug Administration (FDA)-approved drug library, entacapone was identified as a CXCR7 binder. The NanoBit complementation assay was employed to evaluate the effect of entacapone on CXCR7 mediated \u03b2-arrestin 1\/2 recruitment. Molecular docking was performed to predict the binding pocket and binding sites. Results: Entacapone specifically bound to CXCR7 with a Kd value of 6.04 \u00b5M. Although entacapone did not directly activate CXCR7, it selectively inhibited CXCL12 and VUF11207 induced \u03b2-arrestin 1 recruitment with no significant effect on \u03b2-arrestin 2 recruitment. Molecular docking suggested that entacapone interacted with key residues via hydrophobic contacts, including Trp100, Phe124, Gln301, and Leu305, and formed hydrogen bonds with Ser103, Asn108, and Tyr51 in the transmembrane core, collectively suggesting a possible binding mode compatible with stabilizing the receptor in an inactive conformation. Conclusions: Entacapone, a clinically well established COMT inhibitor, is reported for the first time as a novel biased antagonist of CXCR7, providing a new candidate molecule for drug repurposing.<\/jats:p>","DOI":"10.3390\/molecules31152606","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:49:27Z","timestamp":1785131367000},"page":"2606","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Entacapone as a Novel \u03b2-Arrestin 1 Biased Antagonist of CXCR7"],"prefix":"10.3390","volume":"31","author":[{"given":"Liangrui","family":"Shi","sequence":"first","affiliation":[{"name":"College of Pharmaceutical Sciences, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, China"},{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Li","sequence":"additional","affiliation":[{"name":"School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5811-0224","authenticated-orcid":false,"given":"Zenghao","family":"Bi","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junke","family":"Liu","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanyin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaotong","family":"Cong","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bojun","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shilin","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Herbgenomics, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/nrd.2017.178","article-title":"Trends in GPCR drug discovery: New agents, targets and indications","volume":"16","author":"Hauser","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1124\/mol.117.111062","article-title":"G protein-coupled receptors as targets for approved drugs: How many targets and how many drugs?","volume":"93","author":"Sriram","year":"2018","journal-title":"Mol. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/nrd.2016.230","article-title":"A comprehensive map of molecular drug targets","volume":"16","author":"Santos","year":"2017","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.cell.2017.11.033","article-title":"Pharmacogenomics of GPCR drug targets","volume":"172","author":"Hauser","year":"2018","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"eaaq1075","DOI":"10.1126\/scisignal.aaq1075","article-title":"Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation","volume":"11","author":"Smith","year":"2018","journal-title":"Sci. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4808","DOI":"10.1038\/s41467-023-40482-9","article-title":"Molecular insights into intrinsic transducer-coupling bias in the CXCR4-CXCR7 system","volume":"14","author":"Sarma","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1186\/s13578-020-00497-x","article-title":"CXCR7: A \u03b2-arrestin-biased receptor that potentiates cell migration and recruits \u03b2-arrestin2 exclusively through G\u03b2\u03b3 subunits and GRK2","volume":"10","author":"Nguyen","year":"2020","journal-title":"Cell Biosci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1124\/pr.113.007724","article-title":"International Union of Basic and Clinical Pharmacology. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors","volume":"66","author":"Bachelerie","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1073\/pnas.0912852107","article-title":"Beta-arrestin- but not G protein-mediated signaling by the \u201cdecoy\u201d receptor CXCR7","volume":"107","author":"Rajagopal","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Coggins, N.L., Trakimas, D., Chang, S.L., Ehrlich, A., Ray, P., Luker, K.E., Linderman, J.J., and Luker, G.D. (2014). CXCR7 controls competition for recruitment of \u03b2-arrestin 2 in cells expressing both CXCR4 and CXCR7. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0098328"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10828","DOI":"10.1038\/s41467-025-65858-x","article-title":"Constitutive activity of an atypical chemokine receptor revealed by inverse agonistic nanobodies","volume":"16","author":"Otun","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1038\/s41467-020-16664-0","article-title":"The atypical chemokine receptor ACKR3\/CXCR7 is a broad-spectrum scavenger for opioid peptides","volume":"11","author":"Meyrath","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1161\/CIRCULATIONAHA.116.023027","article-title":"Loss of endothelial CXCR7 impairs vascular homeostasis and cardiac remodeling after myocardial infarction: Implications for cardiovascular drug discovery","volume":"135","author":"Hao","year":"2017","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, C., Chen, W., and Shen, J. (2018). CXCR7 targeting and its major disease relevance. Front. Pharmacol., 9.","DOI":"10.3389\/fphar.2018.00641"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1146\/annurev-pharmtox-010919-023340","article-title":"The CXCL12\/CXCR4\/ACKR3 axis in the tumor microenvironment: Signaling, crosstalk, and therapeutic targeting","volume":"61","author":"Smit","year":"2021","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1084\/jem.20102010","article-title":"CXCR7 influences leukocyte entry into the CNS parenchyma by controlling abluminal CXCL12 abundance during autoimmunity","volume":"208","author":"Holman","year":"2011","journal-title":"J. Exp. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"15864","DOI":"10.1021\/acs.jmedchem.0c01588","article-title":"Discovery of the potent, selective, orally available CXCR7 antagonist ACT-1004-1239","volume":"63","author":"Aissaoui","year":"2020","journal-title":"J. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Lounsbury, N. (2020). Advances in CXCR7 modulators. Pharmaceuticals, 13.","DOI":"10.3390\/ph13020033"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e13883","DOI":"10.1111\/cts.13883","article-title":"The effect of itraconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of the first-in-class ACKR3\/CXCR7 antagonist, ACT-1004-1239","volume":"17","author":"Huynh","year":"2024","journal-title":"Clin. Transl. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100085","DOI":"10.1016\/j.molpha.2025.100085","article-title":"Inhibition of constitutive activity of the atypical chemokine receptor 3 by the small-molecule inverse agonist VUF16840","volume":"107","author":"Bosma","year":"2025","journal-title":"Mol. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1007\/s11064-024-04173-1","article-title":"ACKR3 antagonism enhances the repair of demyelinated lesions through both immunomodulatory and remyelinating effects","volume":"49","author":"Pouzol","year":"2024","journal-title":"Neurochem. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"E8652","DOI":"10.1073\/pnas.1811031115","article-title":"QTY code enables design of detergent-free chemokine receptors that retain ligand-binding activities","volume":"115","author":"Zhang","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","first-page":"157","article-title":"Food and Drug Administration","volume":"8","author":"Herwick","year":"1947","journal-title":"J. Am. Pharm. Assoc. Am. Pharm. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.33425\/2692-7918.1067","article-title":"Incidence of adverse events in individuals with Parkinson\u2019s disease treated with monoamine oxidase-B inhibitor safinamide as an add-on to levodopa treatment: A systematic review and meta-analysis","volume":"5","author":"Abola","year":"2024","journal-title":"Neurol. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1039","DOI":"10.1007\/s40120-024-00629-2","article-title":"The catechol O-methyltransferase inhibitor entacapone in the treatment of Parkinson\u2019s disease: Personal reflections on a first-in-class drug development programme 40 years on","volume":"13","author":"Reinikainen","year":"2024","journal-title":"Neurol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.molstruc.2014.03.009","article-title":"MicroScale thermophoresis: Interaction analysis and beyond","volume":"1077","author":"Wanner","year":"2014","journal-title":"J. Mol. Struct."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.ejmech.2012.02.041","article-title":"Synthesis, modeling and functional activity of substituted styrene-amides as small-molecule CXCR7 agonists","volume":"51","author":"Wijtmans","year":"2012","journal-title":"Eur. J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2448","DOI":"10.12998\/wjcc.v8.i12.2448","article-title":"Functions and mechanisms of chemokine receptor 7 in tumors of the digestive system","volume":"8","author":"Xin","year":"2020","journal-title":"World J. Clin. Cases."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Parkinson Study Group (1997). Entacapone improves motor fluctuations in levodopa-treated Parkinson\u2019s disease patients. Ann. Neurol., 42, 747\u2013755.","DOI":"10.1002\/ana.410420511"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1021\/cn400151a","article-title":"Tau-derived-hexapeptide 306VQIVYK311 aggregation inhibitors: Nitrocatechol moiety as a pharmacophore in drug design","volume":"4","author":"Mohamed","year":"2013","journal-title":"ACS Chem. Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e22399","DOI":"10.1096\/fj.202200241RR","article-title":"Entacapone alleviates acute kidney injury by inhibiting ferroptosis","volume":"36","author":"Yang","year":"2022","journal-title":"FASEB J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e22399","DOI":"10.1096\/fasebj.2022.36.S1.R6324","article-title":"Regulation of endothelial cell function by integration of G\u03b1i and \u03b2-arrestin signaling at atypical chemokine receptor 3","volume":"36","author":"Lee","year":"2022","journal-title":"FASEB J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"9049","DOI":"10.1073\/pnas.1018185108","article-title":"Peptide surfactants for cell-free production of functional G protein-coupled receptors","volume":"108","author":"Wang","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5400","DOI":"10.1038\/s41598-022-09217-6","article-title":"An original approach to measure ligand\/receptor binding affinity in non-purified samples","volume":"12","author":"Rascol","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"eabn8063","DOI":"10.1126\/sciadv.abn8063","article-title":"Structures of atypical chemokine receptor 3 reveal the basis for its promiscuity and signaling bias","volume":"8","author":"Yen","year":"2022","journal-title":"Sci. Adv."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2606\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:12:43Z","timestamp":1785211963000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2606"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,26]]},"references-count":35,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152606"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152606","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,26]]}}}