Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Ciancetta, Antonella

doi:10.3390/molecules22030449

Cited by 30 publications

(30 citation statements)

References 61 publications

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“…The identification of A 3 AR chemical modulators would help in the development of novel drugs for the pathologies in which this receptor is involved, such as glaucoma, inflammation, asthma and COPD, as well as several types of cancer. The medicinal chemistry developed around this receptor also responds to growing demand for pharmacological tools to study the (pato)physiology of the A 3 AR, and includes the development of agonists and antagonists, as well as radiolabeled versions of these [ 46 , 47 ].…”

Section: Resultsmentioning

confidence: 99%

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

et al. 2017

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The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A1AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A2AAR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR.

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Section: Resultsmentioning

confidence: 99%

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

et al. 2017

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“…However, there is only one cysteine bridge present in the A 3 AR and the extracellular part of TM2 is expected to be more flexible. Sensibly, a hybrid model basing the TM2 conformation on the activated β2-adrenergic receptor and rhodopsin, better accommodated the ligands with extended C2-substituents [28, 30, 47]. The proposed outer displacement of TM2 logically requires overcoming a greater energy barrier, which might be reflected here in the lower potency of MRS5679.…”

Section: Discussionmentioning

confidence: 99%

Probing structure-activity relationship in β-arrestin2 recruitment of diversely substituted adenosine derivatives

Storme

Tosh

Gao

et al. 2018

Biochemical Pharmacology

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In the adenosine receptor (AR) subfamily of G protein-coupled receptors (GPCRs), biased agonism has been described for the human A1AR, A2BAR and A3AR. While diverse A3AR agonists have been evaluated for receptor binding and Gi-mediated cAMP signalling, the β-arrestin2 (βarr2) pathway has been left largely unexplored. We screened nineteen diverse adenosine derivatives for βarr2 recruitment using a stable hA3AR-NanoBit®-βarr2 HEK293T cell line. Their activity profiles were compared with a cAMP accumulation assay in stable hA3AR CHO cells. Structural features linked to βarr2 activation were further investigated by the evaluation of an additional ten A3AR ligands. The A3AR-selective reference agonist 2-Cl-IB-MECA, which is a full agonist in terms of cAMP inhibition, only showed partial agonist behaviour in βarr2 recruitment. Highly A3AR-selective (N)-methanocarba 5’-uronamide adenosine derivatives displayed higher potency in both cAMP signalling and βarr2 recruitment than reference agonists NECA and 2-Cl-IB-MECA. Their A3AR-preferred conformation tolerates C2-position substitutions, for increased βarr2 efficacy, better than the flexible scaffolds of ribose derivatives. The different amino functionalities in the adenosine scaffold of these derivatives each seem to be important for signalling as well. In conclusion, we have provided insights into ligand features that can help to guide the future therapeutic development of biased A3AR ligands with respect to G-protein and βarr2 signalling.

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“…We did so using class-A GPCR comparative modelling, a well-known bioinformatics strategy aimed at gathering novel structural information on this receptor family that indeed encompasses about 70% of all drug-targets [48,49]. Although GPR17 experimental structure has not been solved yet, the availability of homologous proteins to be used as templates, combined with specific class-A GPCR modelling techniques [50,51], allowed us to obtain an accurate and validated model, with a well-shaped binding site, useful for the subsequent HTS procedures [29,31,36,52,53]. Accordingly, in the very last years, homology modelling has been successfully applied also by other groups for identifying both similar and chemically diverse GPR17 ligands [23,54].…”

Section: Plos Onementioning

confidence: 99%

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

Parravicini¹,

Lecca²,

Marangon³

et al. 2020

PLoS ONE

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The GPR17 receptor, expressed on oligodendroglial precursors (OPCs, the myelin producing cells), has emerged as an attractive target for a pro-myelinating strategy in multiple sclerosis (MS). However, the proof-of-concept that selective GPR17 ligands actually exert protective activity in vivo is still missing. Here, we exploited an iterative drug discovery pipeline to prioritize novel and selective GPR17 pro-myelinating agents out of more than 1,000,000 compounds. We first performed an in silico high-throughput screening on GPR17 structural model to identify three chemically-diverse ligand families that were then combinatorially exploded and refined. Top-scoring compounds were sequentially tested on reference pharmacological in vitro assays with increasing complexity, ending with myelinating OPCneuron co-cultures. Successful ligands were filtered through in silico simulations of metabolism and pharmacokinetics, to select the most promising hits, whose dose and ability to target the central nervous system were then determined in vivo. Finally, we show that, when administered according to a preventive protocol, one of them (named by us as galinex) is able to significantly delay the onset of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. This outcome validates the predictivity of our pipeline to identify novel MS-modifying agents.

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Structural Probing and Molecular Modeling of the A3 Adenosine Receptor: A Focus on Agonist Binding

Cited by 30 publications

References 61 publications

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Probing structure-activity relationship in β-arrestin2 recruitment of diversely substituted adenosine derivatives

Development of the first in vivo GPR17 ligand through an iterative drug discovery pipeline: A novel disease-modifying strategy for multiple sclerosis

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