Molecular docking study of A3 adenosine receptor antagonists and pharmacophore-based drug design

Adenosine is known to act as a neuromodulator by suppressing synaptic transmission in the central and peripheral nervous system. A3 adenosine receptor (A3AR) antagonists were recently considered as potential drugs for the treatment of cardiac ischemia and inflammation diseases. To better understand the chemical features responsible for the recognition mechanism and the receptor–ligand interaction, we have performed the molecular simulation study combined with a virtual library screening process to develop novel A3AR antagonists. A series of A3AR selective antagonists, including triazolopurines, imidazopurines, pyrrolopurines, and quinazolines were employed to dock into the A3AR binding site via AUTODOCK software. The putative binding mode for each compound was proposed. Three main hydrophobic pockets, one hydrogen bonding with Asn250, and one π–π interaction with Phe168 for all antagonists were identified. The most favorable binding conformations served as the templates for pharmacophore modeling with Catalyst 4.11 and a virtually generated library have been screened for novel antagonist development.