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

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.

Changes of the GPR17 receptor, a new target for neurorepair, in neurons and glial cells in patients with traumatic brain injury

“…The purinergic component of GPR17 has been confirmed in two additional independent studies [17,18], whereas response to cysteinyl-leukotrienes has been proposed to be related to the formation of heteromers [17,[19][20][21]. In this respect, in a previous in silico and in vitro study on GPR17 ligands performed by our group [22], we proposed a possible allosteric effect of the CysLT1R antagonist montelukast on GPR17 uracil ligands, suggesting that montelukast may act on a yet uncharacterized binding site differing from the principal orthosteric one.…”

Decoding Signaling and Function of the Orphan G Protein–Coupled Receptor GPR17 with a Small-Molecule Agonist

“…Benned-Jensen and Rosenkilde (23) report a different agonist profile for nucleotide ligands but failed to recapitulate activation by CysLTs, a finding that is in line with other studies that reported lack of agonist activity altogether (20-22, 24) as well as our data in this study. Nevertheless, even a set of five small-molecule agonists identified by virtual screening and proposed to activate GPR17 with high potency (ASINEX ligands 1 to 5) (32) was inactive in our hands and has not been more widely used as research tool for this receptor. Clearly, the pharmacology and function of GPR17 remain rather contentious issues that need to be resolved with a ligand that reliably and reproducibly activates GPR17.…”

A Computational Approach to Evaluate the Androgenic Affinity of Iprodione, Procymidone, Vinclozolin and Their Metabolites

“…Moreover, they are in line with the vision of the 21 st century toxicity paradigm: chemicals will be subjected to a multiplicity of high-throughput screening tests to detect cellular response to an array of “pathways of toxicity”, and results will feed into computational systems biology tools that model dose-response effects and inform new risk assessment approaches [7]. Several computational approaches may be useful for evaluating interactions between a receptor and its putative ligands: some of them are based on molecular docking, which has been reliably used for decades in pharmacological research and development [8], [9].…”