Three-Dimensional Quantitative Structure−Activity Relationship of Nucleosides Acting at the A_3 Adenosine Receptor: Analysis of Binding and Relative Efficacy

Abstract

The binding affinity and relative maximal efficacy of human A_3 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 N^6 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 q^2 values of 0.53 (r^2 = 0.92) and 0.59 (r^2 = 0.92), respectively, and were further validated by an external test set (25 adenosine derivatives), resulting in the best predictive r^2 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 N^6 or C2 position of the adenine ring and a hydrophilic and/or H-bonding group at the 5' position were predicted to increase A_3AR binding affinity. A small hydrophobic group at N^6 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 A_3AR agonists, and the successful conversion of the A_3AR agonist into antagonists by substitution (at N^6) or conformational constraint (at 5'-N-methyluronamide).

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