In silico identification of new ligands for GPR17: a promising therapeutic target for neurodegenerative diseases |
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Authors: | Ivano Eberini Simona Daniele Chiara Parravicini Cristina Sensi Maria L Trincavelli Claudia Martini Maria P Abbracchio |
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Institution: | Gruppo di Studio per la Proteomica e la Struttura delle Proteine, Dipartimento di Scienze Farmacologiche, Università degli Studi di Milano, Italy. ivano.eberini@gmail.com |
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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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