Moro S, Li A H, Jacobson K A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institutes of Health, Bethesda, Maryland 20892-0810, USA.
J Chem Inf Comput Sci. 1998 Nov-Dec;38(6):1239-48. doi: 10.1021/ci980080e.
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.
对多种化学结构各异的人类 A3 腺苷受体拮抗剂（hA3ANTs）进行了分子模拟研究，这些拮抗剂包括腺嘌呤、黄嘌呤、三唑并喹唑啉、黄酮类、噻唑并吡啶、6-苯基-1,4-二氢吡啶和 6-苯基吡啶。通过结合从头算量子力学计算、静电势图比较以及空间和静电排列（SEAL）方法，得出了 hA3ANTs 的通用药效团图。基于所提出的药效团图，我们推测不同 A3 拮抗剂衍生物的受体结合特性是由于在受体结合位点内的一个共同区域的识别，因此具有共同的静电势分布。构建并分析了与三唑并喹唑啉参考配体 CGS 15953（9-氯-2-(2-呋喃基)[1,2,4]三唑并[1,5-c]喹唑啉-5-胺）对接的人类 A3 受体模型，以帮助解释这些结果。根据使用 CGS 15953 的结构作为模板通过空间和静电排列（SEAL）方法获得的结果，将所有其他拮抗剂结构对接至受体内。该受体模型是通过一级序列比较、二级结构预测以及以视紫红质为模板的三维同源性构建而得出的。使用我们最近引入的交叉对接程序（《药物化学杂志》1998 年，41 卷，1456 - 1466 页）获得了配体 - 受体复合物的能量优化三维结构，该程序模拟了配体诱导的天然受体结构的重组。
