J Med Chem. 2019 Jul 11;62(13):5979-6002. doi: 10.1021/acs.jmedchem.8b01651. Epub 2019 Mar 1.
Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. Investigations using allosteric drug candidates and chemical tools suggest that their functional effects may be tailored with a high degree of translational alignment, making them molecular tools to correct pathophysiological functional tone and enable personalized medicine when a causative target-to-disease link is known. We present select examples of functional molecular fine-tuning of allosterism and discuss consequences relevant to drug design.
药物化学家负责将适当的药物靶点特征嵌入临床候选药物的分子结构中。药物与生物靶点结合后，对功能效应进行准确描述是发现新药的基本步骤，可将临床前的疗效和安全性观察结果转化为人体试验。膜结合蛋白，特别是离子通道和 G 蛋白偶联受体 (GPCR)，是易受变构调节的生物靶点。使用变构药物候选物和化学工具进行的研究表明，它们的功能效应可以通过高度的转化一致性进行调整，使其成为在已知因果关系靶点-疾病关联时，纠正病理生理学功能状态和实现个体化医疗的分子工具。我们提出了变构功能分子微调的选择实例，并讨论了与药物设计相关的后果。
