MOLECULAR MODELING STUDIES OF HUMAN A(3) ADENOSINE ANTAGONISTS - STRUCTURAL HOMOLOGY AND RECEPTOR DOCKING

Molecular modeling studies were conducted on various chemically divers e classes of human Ag adenosine receptor antagonists (hA3ANTs), such a s adenines, xanthines, triazoloquinazolines, flavonoids,thiazolopyridi nes, 6-phenyl-1,4-dihydropyridines, and 6-phenylpyridines. Using a com bination of ab initio quantum mechanical calculations, electrostatic p otential map comparison, and the steric and electrostatic alignment (S EAL) method, a general pharmacophore map for hA3ANTs has been derived. Based on the proposed pharmacophore map, we hypothesize that the rece ptor binding properties of different A(3) antagonist derivatives are d ue to recognition at a common region inside the receptor binding site and, consequently, a common electrostatic potential profile. A model o f the human Ag receptor, docked with the triazoloquinazoline reference ligand CGS 15953 2-furyl)[1,2,4]triazolo[1,5-c]quinazolin-5-amine), w as built and analyzed to help interpret these results. All other antag onist structures were docked inside the receptor according to the resu lts obtained through the steric and electrostatic alignment (SEAL) app roach using the structure of CGS 15953 as a template. The receptor mod el was derived from primary sequence comparison, secondary structure p redictions, and three-dimensional homology building, using rhodopsin a s a template. An energetically refined 3D structure of the ligand-rece ptor complex was obtained using our recently introduced cross-docking procedure (J. Med. Chem. 1998, 41, 1456-1466), which simulates the lig and-induced reorganization of the native receptor structure.