A3 adenosine receptor: Homology modeling and 3D-QSAR studies

Abstract

Adenosine receptors (AR) belong to the superfamily of G-protein-coupled receptors (GPCRs). They are divided into four subtypes (A1, A2A, A2B, and A3) and can be distinguished on the basis of their distinct molecular structures, distinct tissues distribution, and selectivity for adenosine analogs. The hA3R, the most recently identified adenosine receptor, is involved in a variety of intracellular signaling pathways and physiological functions. Expression of hA3R was reported to be elevated in cancerous tissues and A3 antagonists could be proposed for therapeutic treatments of tumor. By using the crystal structure of hA2A adenosine receptor, recently published, we were able to obtain a model for A3R, further optimized using nanosecond scale molecular dynamics simulation. One hundred twenty two active and selective compounds were docked into this model and used as training set to generate pharmacophore models. These last address the prevalent features to be used for the search of new inhibitors. Therefore, it was employed as template to screen the ZINC database in the attempt to find new potent and selective human A3R antagonists. Our theoretical model of hA3 adenosine receptor was used to evaluate and quantify the structure-activity relationship of known antagonists. Moreover the obtained 3D-QSAR model allowed to identify new potential inhibitors.