评估配体-受体结合动力学在药物发现中的附加价值。
The Added Value of Assessing Ligand-Receptor Binding Kinetics in Drug Discovery.
作者信息
Guo Dong, Heitman Laura H, IJzerman Adriaan P
机构信息
Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University , 209 Tongshan Road, Xuzhou 221004, Jiangsu, China.
Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University , P.O. Box 9502, 2300 RA Leiden, The Netherlands.
出版信息
ACS Med Chem Lett. 2016 Aug 19;7(9):819-21. doi: 10.1021/acsmedchemlett.6b00273. eCollection 2016 Sep 8.
Abstract
In the past decade drug research community has started to appreciate the indispensable role of ligand-receptor binding kinetics (BK) in drug discovery. Next to the classical equilibrium-based drug evaluation process with affinity and potency values as outcomes, kinetic investigation of the ligand-receptor interaction can aid compound triage in the hit-to-lead campaign and provide additional information to understand the molecular mechanism of drug action. Translational models incorporating BK are emerging as well, which represent powerful tools for the prediction of in vivo effects. In this viewpoint we will summarize some recent findings and discuss and emphasize the added value of ligand-receptor binding kinetics in drug research.
摘要
在过去十年中，药物研究界已开始认识到配体-受体结合动力学（BK）在药物发现中不可或缺的作用。除了以亲和力和效价为结果的基于经典平衡的药物评估过程外，配体-受体相互作用的动力学研究有助于在从苗头化合物到先导化合物的研究过程中对化合物进行分类，并为理解药物作用的分子机制提供额外信息。纳入BK的转化模型也正在兴起，它们是预测体内效应的有力工具。在本观点文章中，我们将总结一些最新发现，并讨论和强调配体-受体结合动力学在药物研究中的附加价值。
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2
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