Pándy-Szekeres G, Caroli J, Mamyrbekov A, Kermani AA, Keserű GM, Kooistra AJ, Gloriam DE (2023) GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources. Nucleic Acids Res 51:D395–D402. https://doi.org/10.1093/nar/gkac1013

Article  PubMed  CAS  Google Scholar 

Congreve M, de Graaf C, Swain NA, Tate CG (2020) Impact of GPCR structures on drug discovery. Cell 181(1):81–91. https://doi.org/10.1016/j.cell.2020.03.003

Article  PubMed  CAS  Google Scholar 

Ballante F, Kooistra AJ, Kampen S, de Graaf C, Carlsson J (2021) Structure-based virtual screening for ligands of G protein–coupled receptors: what can molecular docking do for you? Pharmacol. Rev. 73(4):1698–1736. https://doi.org/10.1124/pharmrev.120.000246

Article  Google Scholar 

Sadybekov AV, Katritch V (2023) Computational approaches streamlining drug discovery. Nature 616:673–685. https://doi.org/10.1038/s41586-023-05905-z

Article  PubMed  CAS  Google Scholar 

Nguyen ATN, Nguyen DTN, Koh HY, Toskov J, MacLean W, Xu A, Zhang D, Webb GI, May LT, Halls ML (2023) The application of artificial intelligence to accelerate G protein-coupled receptor drug discovery. Br. J. Pharmacol. 1– 14. https://doi.org/10.1111/bph.16140

Salmaso V, Jacobson KA (2020) Purinergic signaling: impact of GPCR structures on rational drug design. ChemMedChem 15:1958–1973. https://doi.org/10.1002/cmdc.202000465

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ekins S, Gerlach J, Zorn KM, Antonio BM, Lin Z, Gerlach A (2019a) Repurposing approved drugs as inhibitors of Kv7.1 and Nav1.8 to treat Pitt Hopkins Syndrome. Pharm. Res 36(9):137. https://doi.org/10.1007/s11095-019-2671-y

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ekins S, Puhl AC, Zorn KM, Lane TR, Russo DP, Klein JJ, Hickey AJ, Clark AM (2019b) Exploiting machine learning for end-to-end drug discovery and development. Nat Mater 18(5):435–441. https://doi.org/10.1038/s41563-019-0338-z

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ekins S, Mottin M, Ramos PRPS, Sousa BKP, Neves BJ, Foil DH et al (2020) Déjà vu: Stimulating open drug discovery for SARS-CoV-2. Drug Discov Today 25(5):928–941. https://doi.org/10.1016/j.drudis.2020.03.019

Article  PubMed  PubMed Central  CAS  Google Scholar 

Mock M, Edavettal S, Langmead C, Russell A (2023) AI can help to speed up drug discovery - but only if we give it the right data. Nature 621(7979):467–470. https://doi.org/10.1038/d41586-023-02896-9

Article  PubMed  CAS  Google Scholar 

Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, Miras-Portugal T, Novak I, Schöneberg T, Perez-Sen R, Thor D, Wu B, Yang Z, Müller CE (2020) Update of P2Y receptor pharmacology: IUPHAR Review: 27. Br J Pharmacol 177:2413–2433. https://doi.org/10.1111/bph.15005

Article  PubMed  PubMed Central  CAS  Google Scholar 

Koizumi S, Shigemoto-Mogam Y, Nasu-Tada K, Shinozaki Y, Ohsawa K, Tsuda M, Joshi BV, Jacobson KA, Kohsaka S, Inoue K (2007) UDP acting at P2Y6 receptors is a novel mediator of microglial phagocytosis. Nature 446:1091–1095

Article  PubMed  PubMed Central  CAS  Google Scholar 

Lovászi M, Haas CB, Antonioli L, Pacher P, Haskó G (2021) The role of P2Y receptors in regulating immunity and metabolism. Biochem Pharmacol 187:114419. https://doi.org/10.1016/j.bcp.2021.114419

Article  PubMed  CAS  Google Scholar 

Umpierre AD, Li B, Ayasoufi K, Zhao S, Xie M, Thyen G, Hur B, Zheng J, Liang Y, Wu Z, Yu X, Sung J, Johnson AJ, Li Y, Wu LJ (2023) Microglial P2Y6calcium signaling promotes phagocytosis and shapes neuroimmune responses in epileptogenesis. bioRxiv 544691. https://doi.org/10.1101/2023.06.12.544691

Oliveira-Giacomelli Á, Albino MC, de Souza HDN, Corrêa-Velloso J, de Jesus Santos AP, Baranova J, Ulrich H (2019) P2Y6 and P2X7 receptor antagonism exerts neuroprotective/neuroregenerative effects in an animal model of Parkinson’s disease. Front Cell Neurosci 13:476

Article  PubMed  PubMed Central  CAS  Google Scholar 

Milde S, van Tartwijk FW, Vilalta A et al (2021) Inflammatory neuronal loss in the substantia nigra induced by systemic lipopolysaccharide is prevented by knockout of the P2Y6receptor in mice. J Neuroinflammation 18:225. https://doi.org/10.1186/s12974-021-02280-2

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vieira RP, Müller T, Grimm M, von Gernler V, Vetter B, Dürk T, Cicko S, Ayata CK, Sorichter S, Robaye B, Zeiser R, Ferrari D, Kirschbaum A, Zissel G, Virchow JC, Boeynaems JM, Idzko M (2011) Purinergic receptor type 6 contributes to airway inflammation and remodeling in experimental allergic airway inflammation. Am J Respir Crit Care Med 184:215–223. https://doi.org/10.1164/rccm.201011-1762OC

Article  PubMed  CAS  Google Scholar 

Müller T, Fay S, Vieira RP, Karmouty-Quintana H, Cicko S, Ayata CK, Zissel G, Goldmann T, Lungarella G, Ferrari D, Di Virgilio F, Robaye B, Boeynaems JM, Lazarowski ER, Blackburn MR, Idzko M (2017) P2Y6 receptor activation promotes inflammation and tissue remodeling in pulmonary fibrosis. Front Immunol 8:1028. https://doi.org/10.3389/fimmu.2017.01028

Article  PubMed  PubMed Central  CAS  Google Scholar 

Jain S, Pydi SP, Toti KS, Robaye B, Idzko M, Gavrilova O, Wess J, Jacobson KA (2020) Lack of adipocyte purinergic P2Y6 receptor greatly improves whole body glucose homeostasis. Proc Natl Acad Sci USA 117(48):30763–30774

Article  PubMed  PubMed Central  CAS  Google Scholar 

Salem M, Lecka J, Pelletier J, Gomes Marconato D, Dumas A, Vallières L, Brochu G, Robaye B, Jobin C, Sévigny J (2022) NTPDase8 protects mice from intestinal inflammation by limiting P2Y6 receptor activation: identification of a new pathway of inflammation for the potential treatment of IBD. Gut 71:43–54. https://doi.org/10.1136/gutjnl-2020-320937

Article  PubMed  CAS  Google Scholar 

Zhou M, Wang W, Li Y, Zhang Q, Ji H, Li H, Hu Q (2020) The role of P2Y6R in cardiovascular diseases and recent development of P2Y6R antagonists. Drug Discovery Today 25:568–573. https://doi.org/10.1016/j.drudis.2019.12.015

Article  PubMed  CAS  Google Scholar 

Maruoka H, Barrett MO, Ko H, Tosh DK, Melman A, Burianek LE, Balasubramanian R, Berk B, Costanzi S, Harden TK, Jacobson KA (2010) Pyrimidine ribonucleotides with enhanced selectivity as P2Y6 receptor agonists: Novel 4-alkyloxyimino, (S)-methanocarba, and 5′-triphosphate g-ester modifications. J Med Chem 53:4488–4501

Article  PubMed  PubMed Central  CAS  Google Scholar 

Ginsburg-Shmuel T, Haas M, Schumann M, Reiser G, Kalid O, Stern N, Fischer B (2010) 5-OMe-UDP is a potent and selective P2Y6-receptor agonist. J Med Chem 53(4):1673–1685

Article  PubMed  CAS  Google Scholar 

Ginsburg-Shmuel T, Haas M, Grbic D, Arguin G, Nadel Y, Gendron FP, Reiser G, Fischer B (2012) UDP made a highly promising stable, potent, and selective P2Y6-Receptor agonist upon introduction of a boranophosphate moiety. Bioorg Med Chem 20:5483–5495. https://doi.org/10.1016/j.bmc.2012.07.042

Article  PubMed  CAS  Google Scholar 

Toti KS, Jain S, Ciancetta A, Balasubramanian R, Charkaborty S, Surujdin R, Shi ZD, Jacobson KA (2017) Pyrimidine nucleotides containing a (S)-methanocarba ring as P2Y6 receptor agonists. Med Chem Commun 8:1897–1908

Article  CAS  Google Scholar 

Mamedova L, Joshi BV, Gao ZG, von Kügelgen I, Jacobson KA (2004) Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors. Biochem Pharmacol 67:1763–1770

Article  PubMed  PubMed Central  CAS  Google Scholar 

Nishiyama K, Nishimura A, Shimoda K, Tanaka T, Kato Y, Shibata T, Tanaka H, Kurose H, Azuma YT, Ihara H, Kumagai Y, Akaike T, Eaton P, Uchida K, Nishida M (2022) Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression. Sci. Signaling 15, eabj0644 https://doi.org/10.1126/scisignal.abj0644

Ito M, Egashira S, Yoshida K, Mineno T, Kumagai K, Kojima H, Okabe T, Nagano T, Ui M, Matsuoka I (2017) Identification of novel selective P2Y6 receptor antagonists by high-throughput screening assay. Life Sci 180:137–142. https://doi.org/10.1016/j.lfs.2017.05.017

Article  PubMed  CAS