Abstract
GPR17, a previously orphan receptor responding to both uracil nucleotides and cysteinyl-leukotrienes, has been proposed as a novel promising target for human neurodegenerative diseases. Here, in order to specifically identify novel potent ligands of GPR17, we first modeled in silico the receptor by using a multiple template approach, in which extracellular loops of the receptor, quite complex to treat, were modeled making reference to the most similar parts of all the class-A GPCRs crystallized so far. A high-throughput virtual screening exploration of GPR17 binding site with more than 130,000 lead-like compounds was then applied, followed by the wet functional and pharmacological validation of the top-scoring chemical structures. This approach revealed successful for the proposed aim, and allowed us to identify five agonists or partial agonists with very diverse chemical structure. None of these compounds could have been expected ‘a priori’ to act on a GPCR, and all of them behaved as much more potent ligands than GPR17 endogenous activators.
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Okada T, Sugihara M, Bondar AN, Elstner M, Entel P, Buss V (2004) J Mol Biol 342:571
Jaakola VP, Griffith MT, Hanson MA, Cherezov V, Chien EY, Lane JR, Ijzerman AP, Stevens RC (2008) Science 322:1211
Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK (2007) Nature 450:383
Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007) Science 318:1258
Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007) Science 318:1266
Hanson MA, Cherezov V, Griffith MT, Roth CB, Jaakola VP, Chien EY, Velasquez J, Kuhn P, Stevens RC (2008) Structure 16:897
Warne T, Serrano-Vega MJ, Baker JG, Moukhametzianov R, Edwards PC, Henderson R, Leslie AG, Tate CG, Schertler GF (2008) Nature 454:486
Murakami M, Kouyama T (2008) Nature 453:363
Park JH, Scheerer P, Hofmann KP, Choe HW, Ernst OP (2008) Nature 454:183
Chien EY, Liu W, Zhao Q, Katritch V, Han GW, Hanson MA, Shi L, Newman AH, Javitch JA, Cherezov V, Stevens RC (2010) Science, 330:1091
Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, Stevens RC (2010) Science 330:1066
Jaakola VP, Ijzerman AP (2010) Curr Opin Struct Biol 20:401
Calleri E, Ceruti S, Cristalli G, Martini C, Temporini C, Parravicini C, Volpini R, Daniele S, Caccialanza G, Lecca D, Lambertucci C, Trincavelli ML, Marucci G, Wainer IW, Ranghino G, Fantucci P, Abbracchio MP, Massolini G (2010) J Med Chem 53:3489
Brink C (2003) Adv Exp Med Biol 525:7
Ciana P, Fumagalli M, Trincavelli ML, Verderio C, Rosa P, Lecca D, Ferrario S, Parravicini C, Capra V, Gelosa P, Guerrini U, Belcredito S, Cimino M, Sironi L, Tremoli E, Rovati GE, Martini C, Abbracchio MP (2006) EMBO J 25:4615
Pugliese AM, Trincavelli ML, Lecca D, Coppi E, Fumagalli M, Ferrario S, Failli P, Daniele S, Martini C, Pedata F, Abbracchio MP (2009) Am J Physiol Cell Physiol 297:C1028
Lecca D, Trincavelli ML, Gelosa P, Sironi L, Ciana P, Fumagalli M, Villa G, Verderio C, Grumelli C, Guerrini U, Tremoli E, Rosa P, Cuboni S, Martini C, Buffo A, Cimino M, Abbracchio MP (2008) PLoS One 3:e3579
Ceruti S, Villa G, Genovese T, Mazzon E, Longhi R, Rosa P, Bramanti P, Cuzzocrea S, Abbracchio MP (2009) Brain 132:2206
Chen Y, Wu H, Wang S, Koito H, Li J, Ye F, Hoang J, Escobar SS, Gow A, Arnett HA, Trapp BD, Karandikar NJ, Hsieh J, Lu QR (2009) Nat Neurosci 12:1398
Chenna R, Sugawara H, Koike T, Lopez R, Gibson TJ, Higgins DG, Thompson JD (2003) Nucleic Acids Res 31:3497
Eldesbrunner H, Facello M, Fu R, Liang J (1995) In: Proceedings of the 28th Hawaii international conference on systems science
Wojciechowski M, Lesyng B (2004) J. Phys. Chem. B 108:18368
Fumagalli M, Trincavelli L, Lecca D, Martini C, Ciana P, Abbracchio MP (2004) Biochem Pharmacol 68:113
Niv MY, Skrabanek L, Filizola M, Weinstein H (2006) J Comput Aided Mol Des 20:437
Costanzi S (2008) J Med Chem 51:2907
Katritch V, Jaakola VP, Lane JR, Lin J, Ijzerman AP, Yeager M, Kufareva I, Stevens RC, Abagyan R (2010) J Med Chem 53:1799
Peeters MC, van Westen GJ, Li Q, Ijzerman AP (2011) Trends Pharmacol Sci 32:35
Parravicini C, Abbracchio MP, Fantucci P, Ranghino G (2010) BMC Struct Biol 10:8
Parravicini C, Ranghino G, Abbracchio MP, Fantucci P (2008) BMC Bioinformatics 9:263
Frishman D, Argos P (1996) Protein Eng 9:133
Frishman D, Argos P (1997) Proteins 27:329
Thompson MJ, Goldstein RA (1997) Protein Sci 6:1963
Jones DT (1999) J Mol Biol 292:195
Cheng J, Randall AZ, Sweredoski MJ, Baldi P (2005) Nucleic Acids Res 33:W72
Globisch C, Pajeva IK, Wiese M (2008) ChemMedChem 3:280
Bondensgaard K, Ankersen M, Thogersen H, Hansen BS, Wulff BS, Bywater RP (2004) J Med Chem 47:888
Vilar S, Karpiak J, Costanzi S (2010) J Comput Chem 31:707
Eberini I, Rocco AG, Mantegazza M, Gianazza E, Baroni A, Vilardo MC, Donghi D, Galliano M, Beringhelli T (2008) J Mol Graph Model 26:1004
Eberini I, Fantucci P, Rocco AG, Gianazza E, Galluccio L, Maggioni D, Ben ID, Galliano M, Mazzitello R, Gaiji N, Beringhelli T (2006) Proteins 65:555
Ricchiuto P, Rocco AG, Gianazza E, Corrada D, Beringhelli T, Eberini I (2008) J Mol Recognit 21:348
Brink C, Dahlen SE, Drazen J, Evans JF, Hay DW, Nicosia S, Serhan CN, Shimizu T, Yokomizo T (2003) Pharmacol Rev 55:195
Melani A, Turchi D, Vannucchi MG, Cipriani S, Gianfriddo M, Pedata F (2005) Neurochem Int 47:442
Ciceri P, Rabuffetti M, Monopoli A, Nicosia S (2001) Br J Pharmacol 133:1323
Acknowledgments
This work was partially supported by Progetti di Ricerca di Interesse Nazionale COFIN-PRIN 2008, Ministero dell’Istruzione dell’Università e della Ricerca “Purinoceptors and neuroprotection: focus on the new purinergic receptor GPR17” to MPA and MLT. CP is recipient of a Cariplo Foundation fellowship (“Promuovere progetti internazionali finalizzati al reclutamento di giovani ricercatori”, Project N. 2008.2907 to MPA).
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Ivano Eberini, Simona Daniele, Chiara Parravicini equally contributed to this work.
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Eberini, I., Daniele, S., Parravicini, C. et al. In silico identification of new ligands for GPR17: a promising therapeutic target for neurodegenerative diseases. J Comput Aided Mol Des 25, 743–752 (2011). https://doi.org/10.1007/s10822-011-9455-8
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DOI: https://doi.org/10.1007/s10822-011-9455-8