Structure-based virtual screening discovers potent and selective adenosine A1 receptor antagonists

Development of subtype-selective leads is essential in drug discovery campaigns targeting G protein-coupled receptors (GPCRs). Herein, a structure-based virtual screening approach to rationally design subtype-selective ligands was applied to the A1 and A2A adenosine receptors (A1R and A2AR). Crystal structures of these closely related subtypes revealed a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. A library of 4.6 million compounds was screened computationally against both receptors using molecular docking and 20 A1R selective ligands were predicted. Of these, seven antagonized the A1R with micromolar activities and several compounds displayed slight selectivity for this subtype. Twenty-seven analogs of two discovered scaffolds were designed, resulting in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. Our results show the potential of structure-based virtual screening to guide discovery and optimization of subtype-selective ligands, which could facilitate the development of safer drugs.

Automated summary

A structure-based virtual screening approach was used to design subtype-selective ligands for A1 and A2A adenosine receptors. The study identified a non-conserved subpocket in the binding sites that could be exploited to identify A1R selective ligands. Computational screening predicted 20 A1R selective ligands, with 7 of them exhibiting micromolar activities against A1R. Further optimization resulted in antagonists with nanomolar potency and up to 76-fold A1R-selectivity. This study demonstrates the potential of structure-based virtual screening in guiding the discovery and optimization of subtype-selective ligands, enabling the development of safer drugs.