In silico investigation of the selectivity mechanism of A1AR and A2AAR antagonism

Abstract

Adenosine A₁ receptor (A₁AR) and adenosine A_2A receptor (A_2AAR) are AR isoforms that share high homology but play many different roles in terms of regulating arteriolar pressure and urine flow as well as relieving neurodegenerative disorders. Because A₁AR and A_2AAR have such varied distributions and biological functions, it is critical to distinguish their inhibitory selectivity to minimize unwanted side effects. Thereby, multiple in silico methodologies were used to reveal interactions between key amino acids and selective inhibitors to elucidate the mechanism of selective inhibition towards A₁AR and A_2AAR. Our results indicated that although A₁AR has conserved PHE171 and ASN254, which are also present in A_2AAR, namely PHE168 and ASN253, the two isoforms have different binding patterns towards their inhibitors. Generally, A_2AAR inhibitors interact with GLU169 via hydrogen bonds, whereas A₁AR inhibitors have no corresponding effect. Taken together, our data comprehensively elaborated the selectivity mechanisms of A₁AR and A_2AAR inhibition, which presents a reasonable guidance, significant for the rational design of selective inhibitors towards A₁/A_2AAR.