Molecular Modeling Section (MMS), Department of Pharmaceutical Sciences, University of Padova, 35131 Padova, Italy.
Curr Pharm Des. 2009;15(35):4069-84. doi: 10.2174/138161209789824777.
The development of ligands for the A(3) adenosine receptor (AR) has been directed mainly by traditional medicinal chemistry, but the influence of structure-based approaches is increasing. Rhodopsin-based homology modeling had been used for many years to obtain three-dimensional models of the A(3)AR, and different A(3)AR models have been published describing the hypothetical interactions with known A(3)AR ligands having different chemical scaffolds. The recently published structure of the human A(2A)AR provides a new template for GPCR modeling, however even use of the A(2A)AR as a template for modeling other AR subtypes is still imprecise. The models compared here are based on bovine rhodopsin, the human beta(2)-adrenergic receptor, and the A(2A)AR as templates. The sequence of the human A(3)AR contains only one cysteine residue (Cys166) in the second extracellular loop (EL2), which putatively forms a conserved disulfide bridge with the respective cysteine residues of TM3 (Cys83). Homology models of the A(3)AR have been helpful in providing structural hypotheses for the design of new ligands. Site-directed mutagenesis of the A(3)AR shows an important role in ligand recognition for specific residues in TM3, TM6 and TM7.
A(3) 腺苷受体 (AR) 配体的开发主要由传统的药物化学指导，但基于结构的方法的影响正在增加。基于视紫红质的同源建模多年来一直用于获得 A(3)AR 的三维模型，并且已经发表了不同的 A(3)AR 模型，描述了与具有不同化学支架的已知 A(3)AR 配体的假设相互作用。最近发表的人类 A(2A)AR 的结构为 GPCR 建模提供了一个新的模板，然而，即使使用 A(2A)AR 作为建模其他 AR 亚型的模板仍然不够精确。这里比较的模型是基于牛视紫红质、人β 2-肾上腺素能受体和 A(2A)AR 作为模板。人 A(3)AR 的序列在第二细胞外环 (EL2) 中仅含有一个半胱氨酸残基 (Cys166)，推测它与 TM3(Cys83)的相应半胱氨酸残基形成保守的二硫键。A(3)AR 的同源模型有助于为设计新的配体提供结构假设。A(3)AR 的定点突变显示 TM3、TM6 和 TM7 中的特定残基在配体识别中起重要作用。
