Novel Strategies for the Design of New Potent and Selective Human A3 Receptor Antagonists: An Update

Abstract

A computer-aided approach has been developed in order to understand the molecular pharmacology of human A3R, and specifically, to lead to the discovery and structural refinement of new, potent and selective human A3R antagonists. This review focuses on our combined target-based and ligand-based drug design strategy, recently applied to provide more accurate information about the recognition mode on human A3R of some pyrazolotriazolopyrimidine and triazoloquinoxalinone analogs. The 3D rhodopsin-based homology model of human A3R has represented the starting point of our approach. A high throughput molecular docking method on the considered antagonists has allowed us to generate a receptor-based pharmacophore model. A novel "Y-shaped" pharmacophore binding motif has been proposed for both pyrazolotriazolopyrimidine and triazoloquinoxalinone derivatives. Moreover, related receptor-based 3D-QSAR analysis has been carried out to provide a suitable tool for prediction of the antagonists binding affinity on human A3R.

Ligand and structure-based methodologies for the prediction of the activity of G protein-coupled receptor ligands

“…On the basis of this model, the authors designed, synthesized, and tested a set of novel compounds. The experimentally determined affinities of the novel antagonists were remarkably close to their predicted values, with an r 2 of 0.873 [37,48].…”

“…Dealing with crystal structures of nuclear hormone receptors and enzymes, Sippl amply demonstrated the advantages of combining the accuracy of ligand alignments obtained through docking with the computational efficiency of 3D-QSAR methodologies [84][85][86][87]. Receptorbased 3D-QSAR -in which receptor-ligand complexes are not used to directly calculate binding interactions, but only to generate the 3D alignment of the ligands -has also been applied successfully to GPCRs, by means of docking studies conducted at homology models derived using rhodopsin as a structural template [7,37,44,48,[88][89][90][91]. Notably, Moro and coworkers adopted this approach to obtain a quantitative model for the prediction of the activities of antagonists of the human A 3 receptor.…”

“…Furthermore, spatial autocorrelation vectors offer the advantage of being independent of the 3D orientation of the molecules. On these bases, Moro and coworkers recently introduced the autocorrelation of molecular electrostatic surface properties combined with partial least square analysis (autoMEP/PLS) as an attractive alternative to CoMFA [36,[47][48][49]. The authors applied the novel strategy to the study of the activity of antagonists of the adenosine A 3 receptor.…”

Pyrimidine Derivatives as Potent and Selective A3 Adenosine Receptor Antagonists

“…[11][12][13][14][15][16][17][18] The search for A 3 AR antagonists began with the observation that xanthines ; a successful structural motif in the search for antagonists for the other ARs subtypes ; exhibit low binding affinities for the A 3 receptor subtype. The pursuit of A 3 AR antagonists therefore focused on the exploration of structurally diverse heterocyclic libraries.…”

“…Nowadays, the best known class of A 3 AR ligands ( Figure 1) includes highly diverse families of tri-and bicyclic heteroaromatic scaffolds and, to a lesser extent, mono-heterocyclic systems. Whereas the systematic structural elaboration of these prototypes has provided derivatives possessing good affinity, [11][12][13][14][15][16][17][18] the selectivity issue and the relatively poor bioavailability profiles of drug candidates have remained elusive until recently. [5][6][7] The pyrimidine core, being part of the heterocyclic moiety of the endogenous ligand of these receptors (adenosine), is a recurrent substructural motif within bi-and tricyclic ARs antagonists.…”