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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease
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Quantifying ligand-receptor interactions for gorge-spanning acetylcholinesterase inhibitors for the treatment of Alzheimer's disease

机译：定量用于跨越性乙酰胆碱酯酶抑制剂治疗阿尔茨海默氏病的配体-受体相互作用

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摘要

There is a need for continued development of acetylcholinesterase (AChE) inhibitors that could prolong the life of acetylcholine in the synaptic cleft and also prevent the aggregation of amyloid peptides associated with Alzheimer's disease. The lack of a 3D-QSAR model which specifically deconvulates the type of interactions and quantifies them in terms of energies has motivated us to report a CoRIA model vis-a-vis the standard 3D-QSAR methods, CoMFA and CoMSIA. The CoRIA model was found to be statistically superior to the CoMFA and CoMSIA models and it could efficiently extract key residues involved in ligand recognition and binding to AChE. These interactions were quantified to gauge the magnitude of their contribution to the biological activity. In order to validate the CoRIA model, a pharmacophore map was first constructed and then used to virtually screen public databases, from which novel scaffolds were cherry picked that were not present in the training set. The biological activities of these novel molecules were then predicted by the CoRIA, CoMFA, and CoMSIA models. The hits identified were purchased and their biological activities were measured by the Ellman's method for AChE inhibition. The predicted activities are in unison with the experimentally measured biological activities.
机译：需要持续开发乙酰胆碱酯酶（AChE）抑制剂，其可延长乙酰胆碱在突触间隙中的寿命，并防止与阿尔茨海默氏病相关的淀粉样肽的聚集。缺乏3D-QSAR模型，该模型特别消除了相互作用的类型并根据能量进行了量化，这促使我们针对标准3D-QSAR方法，CoMFA和CoMSIA报告了CoRIA模型。发现CoRIA模型在统计学上优于CoMFA和CoMSIA模型，并且可以有效地提取参与配体识别和与AChE结合的关键残基。对这些相互作用进行了定量，以评估它们对生物活性的贡献程度。为了验证CoRIA模型，首先构建了药效团图，然后将其用于虚拟筛选公共数据库，从中筛选出训练集中不存在的新颖支架。然后通过CoRIA，CoMFA和CoMSIA模型预测这些新型分子的生物学活性。购买确定的命中物，并通过Ellman抑制AChE的方法测量其生物学活性。预测的活动与实验测量的生物活动一致。

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