## 1 Introduction  
Adenosine is a key extracellular signaling molecule that regulates the cellular responses to tissue damage, hypoxia, and energy depletion, through activation of G protein-coupled receptors [1]. To date, four adenosine receptor (AR) subtypes have been identified and pharmacologically characterized: A\({}_{1}\) A\({}_{2A}\), A\({}_{2B}\), and A\({}_{3}\). These receptors are ubiquitously expressed on almost all cell types [1]. Retrospectively, the human A\({}_{3}\) AR subtype (hA\({}_{3}\) AR) was the last member of the adenosine family to have been cloned. It was originally described in 1991 by [PERSON] and collaborators as an orphan receptor from rat testis and coded as tgpcr1, sharing 40% of sequence similarity with canine A\({}_{1}\) and A\({}_{2A}\) ARs [2]. One year later, [PERSON] and collaborators described the cDNA sequence, initially named R226 and extracted from the rat striatum, that encoded for a G protein-coupled receptor with an identical sequence of tgpcr1 and able to bind adenosine [3]. This experimental evidence led to the conclusion that it was a new AR subtype, namely A\({}_{3}\). In the last decades, the field of the therapeutic application in targeting the hA\({}_{3}\) AR represents a rapidly growing area of research in adenosine field, both agonists and antagonists have been described to have a potential application in the treatment of several diseases, e.g. glaucoma, cancer,and autoimmune inflammations [4]. In particular, hA\({}_{3}\) AR agonists have been recently described as promising antinociceptive agents in different preclinical models of chronic pain [5] and in clinical trials as drug candidates for treating psoriasis, rheumatoid arthritis, and hepatocellular carcinoma [6]. In addition, hA\({}_{3}\) AR antagonists were described as potential drug candidates for the treatment of respiratory tract inflammations, such as asthma [7] and glaucoma [8]. As recently reviewed by several authors, in the recent past structure-based molecular modeling approaches, above all molecular docking, have been increasingly applied in rationalizing the structure-activity relationships (SARs) of both agonists and antagonists and in supporting the design of novel potent and selective hA\({}_{3}\) AR ligands [9]. More recently, molecular dynamics (MD) simulations have been performed to elucidate the ligand recognition at the hA\({}_{3}\) AR [10]. To date, the most severe fact that limits the accuracy of the structure-based molecular modeling approaches is due to the fact that the three-dimensional hA\({}_{3}\) AR structure has not been solved yet. The first fundamental breakthrough in this field is the disclosure of the first structure of the hA\({}_{2A}\) AR, a close homolog, which allowed the construction of three-dimensional models for homology by an accuracy level much higher than before, in terms of sequence identity and resolution of the available templates [11]. Following the publication of the first structure, the availability of novel crystallographic information of hA\({}_{2A}\) AR in complexes with both agonists and antagonists are contributing to increase the knowledge at the molecular level of ligand recognition at ARs, leading, finally, to an increased applicability domain and accuracy of structure-based ligand design (SBLD) approaches (not only in the adenosine field). Nowadays, just 46 crystal structures are already available, bound to a wide variety of agonists and antagonists that are either natural or synthetic, and representing the majority of structural determinants on adenosine receptors ligands' activity. However, dealing with the hA\({}_{3}\) AR at a molecular level is still challenging, because the accuracy of the hA\({}_{3}\) AR model strongly depends on the sequence identity/similarity and resolution of the available crystallographic templates used for its construction.