Molecular modeling studies of human A3 adenosine antagonists: structural homology and receptor docking.

Molecular modeling studies were conducted on various chemically diverse classes of human A3 adenosine receptor antagonists (hA3ANTs), such as adenines, xanthines, triazoloquinazolines, flavonoids, thiazolopyridines, 6-phenyl-1, 4-dihydropyridines, and 6-phenylpyridines. Using a combination of ab initio quantum mechanical calculations, electrostatic potential map comparison, and the steric and electrostatic alignment (SEAL) method, a general pharmacophore map for hA3ANTs has been derived. Based on the proposed pharmacophore map, we hypothesize that the receptor binding properties of different A3 antagonist derivatives are due to recognition at a common region inside the receptor binding site and, consequently, a common electrostatic potential profile. A model of the human A3 receptor, docked with the triazoloquinazoline reference ligand CGS 15953 (9-chloro-2-(2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine), was built and analyzed to help interpret these results. All other antagonist structures were docked inside the receptor according to the results obtained through the steric and electrostatic alignment (SEAL) approach using the structure of CGS 15953 as a template. The receptor model was derived from primary sequence comparison, secondary structure predictions, and three-dimensional homology building, using rhodopsin as a template. An energetically refined 3D structure of the ligand-receptor complex was obtained using our recently introduced cross-docking procedure (J. Med. Chem. 1998, 41, 1456-1466), which simulates the ligand-induced reorganization of the native receptor structure.