Three-dimensional quantitative structure-activity relationship of nucleosides acting at the A3 adenosine receptor: analysis of binding and relative efficacy

The binding affinity and relative maximal efficacy of human A3 Adenosine Receptor (AR) agonists were each subjected to ligand-based three-dimensional quantitative structure-activity relationship analysis. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) used as training sets a series of 91 structurally diverse adenosine analogues with modifications at the N6 and C2 positions of the adenine ring and at the 3', 4', and 5' positions of the ribose moiety. The CoMFA and CoMSIA models yielded significant cross-validated q2 values of 0.53 (r2 = 0.92) and 0.59 (r2 = 0.92), respectively, and were further validated by an external test set (25 adenosine derivatives), resulting in the best predictive r2 values of 0.84 and 0.70 in each model. Both the CoMFA and the CoMSIA maps for steric or hydrophobic, electrostatic, and hydrogen-bonding interactions well reflected the nature of the putative binding site previously obtained by molecular docking. A conformationally restricted bulky group at the N6 or C2 position of the adenine ring and a hydrophilic and/or H-bonding group at the 5' position were predicted to increase A3AR binding affinity. A small hydrophobic group at N6 promotes receptor activation. A hydrophilic and hydrogen-bonding moiety at the 5' position appears to contribute to the receptor activation process, associated with the conformational change of transmembrane domains 5, 6, and 7. The 3D-CoMFA/CoMSIA model correlates well with previous receptor-docking results, current data of A3AR agonists, and the successful conversion of the A3AR agonist into antagonists by substitution (at N6) or conformational constraint (at 5'-N-methyluronamide).