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人类尼古丁型乙酰胆碱受体α7亚型是精神分裂认知障碍的治疗靶点,开发具有选择性的激动剂对于该疾病的临床治疗具有重要意义。由于α7受体的三维结构尚未解析,我们采取基于配体的药物设计策略,用HypoGen方法构建了该受体激动剂的药效团模型,并通过费用函数(cost function)进行质量评价,以测试集活性预测和基于Fisher随机化方法的交互检验进行药效团验证。通过富集因子(EF)和ROC曲线下面积(AU-ROC)等统计学参数挑选得到的最终药效团模型具有1个氢键受体(HBA),2个疏水中心(Hydrophobic)和1个正电离子化基团(PosIonizable),并且该药效团模型和α7受体同源模建蛋白的配体对接结果的吻合度较好。本研究所建立的药效团模型,可用于后续α7受体选择性激动剂的筛选和优化,对抗精神分裂疾病药物的开发具有一定的理论指导和应用价值。
The human nicotinic acetylcholine receptor α7 subtype is a therapeutic target for schizoaffective cognition disorders. Developing selective agonists is of great importance for the clinical treatment of this disease. Since the three-dimensional structure of the α7 receptor has not been resolved, we adopt a ligand-based drug design strategy and construct a pharmacophore model of this receptor agonist using the HypoGen method and evaluate the quality by a cost function to test Set Activity Prediction and Fisher Randomization Based Interaction Test for Pharmacodynamic Validation. The final pharmacophore model, which was selected by statistical parameters such as enrichment factor (EF) and area under the ROC curve (AU-ROC), had one hydrogen bond acceptor (HBA), two hydrophobic centers and one Positive ionization group (PosIonizable), and the pharmacophore model and the α7 receptor homologous protein docking results of ligand match better. The pharmacophore model established in this study can be used for the screening and optimization of selective α7 receptor selective agonists, and has certain theoretical guidance and application value for the development of drugs against schizophrenia.