Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

摘要: The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled (GPCRs). They mediate a number (patho)physiological functions have attracted interest biopharmaceutical sector decades as potential drug targets. many crystal structures lately A1 allow use advanced computational, structure-based ligand design methodologies. Over last decade, we assessed efficient synthesis novel ligands specifically addressed each ARs. We herein review update results this program with particular focus on molecular dynamics (MD) free energy perturbation (FEP) protocols. first in silico mutagenesis A1AR here reported allows understanding specificity high affinity xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On A2AAR, demonstrate how FEP simulations can distinguish conformational selectivity recent series partial agonists. These are complemented revision enantiospecific antagonists A2BAR, tool bioisosteric A3AR.