IJzerman A P, Van Galen P J, Jacobson K A
Center for Bio-Pharmaceutical Sciences, Division of Medicinal Chemistry, Leiden, The Netherlands.
Drug Des Discov. 1992;9(1):49-67.
The amino acid sequence of the canine adenosine A1 receptor and the atomic coordinates of a structurally related protein, bacteriorhodopsin, were combined to generate a three-dimensional model for the adenosine A1 receptor. This model consists of seven amphipathic alpha-helices, forming a pore that has a rather distinct partition between hydrophobic and hydrophilic regions. Subsequently, a highly potent and selective ligand, N6-cyclopentyladenosine, was docked into this cavity. A binding site is proposed that takes into account the conformational characteristics of the ligand, obtained from indirect modeling studies by the 'active analog approach'. Moreover, it involves two histidine residues that were shown to be important for ligand coordination from chemical modification studies. Finally, the deduced binding site was used to model other potent ligands that could all be accommodated consistent with earlier biochemical and pharmacological findings.
犬腺苷A1受体的氨基酸序列与结构相关蛋白细菌视紫红质的原子坐标相结合，生成了腺苷A1受体的三维模型。该模型由七个两亲性α螺旋组成，形成一个在疏水和亲水区域之间有相当明显分隔的孔。随后，一种高效且选择性的配体N6-环戊基腺苷被对接至该腔内。提出了一个结合位点，该位点考虑了通过“活性类似物方法”的间接建模研究获得的配体构象特征。此外，它涉及两个组氨酸残基，化学修饰研究表明这两个残基对配体配位很重要。最后，推导得到的结合位点被用于对其他强效配体进行建模，这些配体都能与早期的生化和药理学研究结果一致地容纳。
