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Polypharmacology of conformationally locked methanocarba nucleosides
Drug Discovery Today ( IF 6.5 ) Pub Date : 2017-08-03 , DOI: 10.1016/j.drudis.2017.07.013
Kenneth A Jacobson 1 , Dilip K Tosh 1 , Kiran S Toti 1 , Antonella Ciancetta 1
Affiliation  

A single molecular scaffold can be adapted to interact with diverse targets, either separately or simultaneously. Nucleosides and nucleotides in which ribose is substituted with bicyclo[3.1.0]hexane are an example of a versatile drug-like scaffold for increasing selectivity at their classical targets: kinases, polymerases, adenosine and P2 receptors. Also, by applying structure-based functional group manipulations, rigidified adenosine derivatives can be repurposed to satisfy pharmacophoric requirements of various GPCRs, ion channels, enzymes and transporters, initially detected as off-target activities. Recent examples include 5HT2B serotonin receptor antagonists and novel dopamine transporter allosteric modulators. This directable target diversity establishes rigid nucleosides as privileged scaffolds.



中文翻译:


构象锁定甲烷卡巴核苷的多药理学



单个分子支架可以单独或同时与不同的靶标相互作用。核糖被双环[3.1.0]己烷取代的核苷和核苷酸是多功能类药物支架的一个例子,用于提高其经典靶点的选择性:激酶、聚合酶、腺苷和P2受体。此外,通过应用基于结构的官能团操作,刚性化腺苷衍生物可以重新利用,以满足各种 GPCR、离子通道、酶和转运蛋白的药效学要求,最初检测为脱靶活性。最近的例子包括 5HT 2B血清素受体拮抗剂和新型多巴胺转运蛋白变构调节剂。这种可定向的靶标多样性将刚性核苷建立为优先支架。

更新日期:2017-08-03
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