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In silico identification of new ligands for GPR17: a promising therapeutic target for neurodegenerative diseases

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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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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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Authors and Affiliations

  1. Gruppo di Studio per la Proteomica e la Struttura delle Proteine, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133, Milano, Italy

    Ivano Eberini & Cristina Sensi

  2. Laboratorio di Farmacologia Molecolare e Cellulare della Trasmissione Purinergica, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Via Giuseppe Balzaretti 9, 20133, Milano, Italy

    Chiara Parravicini & Maria P. Abbracchio

  3. Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Università degli Studi di Pisa, Via Bonanno Pisano 6, 56126, Pisa, Italy

    Simona Daniele, Maria L. Trincavelli & Claudia Martini

Authors
  1. Ivano Eberini
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  2. Simona Daniele
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  3. Chiara Parravicini
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  4. Cristina Sensi
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  5. Maria L. Trincavelli
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  6. Claudia Martini
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  7. Maria P. Abbracchio
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Corresponding author

Correspondence to Ivano Eberini.

Additional information

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

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