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目的:建立多巴胺受体三维结构模型,结合受体模型从分子水平上研究四氢原小檗碱类(THPB)对多巴胺受体的作用机制。方法:以细菌视紫红质的三维结构为模板,在计算机上建立多巴胺D_1和D_2受体的三维结构模型,选择左旋千金藤立定作为THPB的先导化合物,将它分别对接到D_1和D_2受体的结合位点。结果:得到了配体-受体相互作用模型,提出了THPB对多巴胺受体可能的作用机制,即配体上质子化N原子与受体第三个跨膜结构的Asp残基形成静电和氢键作用,配体D环上两个取代基与受体第五个跨膜结构的两个Ser残基分别形成氢键作用,配体上芳香环与围绕配体的芳香残基形成π—π相互作用。结论:该配体-受体相互作用模型具有一定程度的合理性,将有助于设计作用更强的药物。
OBJECTIVE: To establish a three-dimensional structure model of dopamine receptors and study the mechanism of action of tetrahydroprotoberberines (THPB) on dopamine receptors at the molecular level in combination with the receptor model. Methods: The three-dimensional structure model of dopamine D_1 and D_2 receptors was established by using the three-dimensional structure of bacteriorhodopsin as a template. The three-dimensional structure model of dopamine D_1 and D_2 receptors was established on the computer and selected as the lead compound of THPB, which was docked to D_1 and D_2 receptors respectively Binding site. Results: The ligand-receptor interaction model was obtained and the possible mechanism of action of THPB on dopamine receptors was proposed. That is, the protonated N atom on the ligand and the Asp residue on the third transmembrane structure of the receptor formed electrostatic and hydrogen Bond, the two substituents on the D ring of the ligand form hydrogen bonds with the two Ser residues of the fifth transmembrane structure of the receptor, respectively, and the aromatic ring in the ligand forms π-π with the aromatic residues surrounding the ligand interaction. CONCLUSIONS: This ligand-receptor interaction model is reasonable to some extent and will help to design more potent drugs.