Structural Predictions of Adenosine 2B Antagonist Affinity Using Molecular Field Analysis

Abstract

3D structural evaluation of the adenosine 2B (A2B) antagonist binding site is the major aim for developing specific selective antagonists. In an attempt to deduce structural properties of the antagonist site, a pharmacophore model was developed using 85 known A2B antagonists. The molecular mechanics optimization methods were used to deduce the likely binding conformations of the antagonists at the binding site. Superimposition of the antagonists was carried out using fit-atoms. This alignment was used to develop CoMFA models of the A2B antagonist binding site. The models possessed promising predictive ability as indicated by the high cross-validated correlation (q2=0.752, r2=0.982) and the prediction on the external test set. The analyses showed that steric and electrostatic interactions contributed to A2B antagonist biological activity equally. The hydrogen-bond donor nature of the 7-position of xanthine (1∼68) and 3-position of alloxazine (83) was essential for the biological activity. In addition, the presence of more negative charges on the 1-N position of xanthine and 10-N position of alloxazine increases biological activity. The bulky aromatic substitutions on the 8-position of xanthine compounds improve activity, while an alkyl substitution on the 1-position of alloxazine might enhance activity. The model generated from this investigation produced important structural requirements, which will be used to optimize the structural complementarity of the antagonists at the A2B binding site.