药效团
二价(发动机)
兴奋剂
DNA
计算生物学
化学
变构调节
组合化学
立体化学
受体
生物物理学
生物化学
生物
有机化学
金属
作者
Na Zhao,Wenwei Wu,Ying Wang,Kun Song,Gaoxian Chen,Yingzhi Chen,Ruowen Wang,Jianrong Xu,Kai Cui,Hongzhuan Chen,Tan Wang,Jian Zhang,Zeyu Xiao
出处
期刊:Chem
[Elsevier]
日期:2023-04-01
卷期号:9 (4): 901-923
被引量:5
标识
DOI:10.1016/j.chempr.2022.12.002
摘要
Great interest is focused on the construction of bivalent ligands, where the spacer is crucial to coordinate the distance and orientation of two pharmacophores for optimal biological effects. Current strategies rely on polymers as spacers but suffer from the paucity of structural precision and variability with time-consuming ligation procedures. Herein, we originate a DNA-modularized strategy where pharmacophores are modularly modified with the protecting groups used for automatic DNA synthesis while natural deoxynucleotides serve as spacers. By programmably regulating the number and permutation of the bridged DNA spacer, the two pharmacophores are adjusted with a defined distance and versatile orientation. Using this strategy, we successfully constructed a reservoir of bivalent ligands containing an orthosteric agonist and an allosteric modulator, exhibiting a single-nucleotide difference in the selective activation of muscarinic acetylcholine receptors. Our strategy opens a new avenue for the precise construction and efficient screening of bivalent ligands toward a myriad of biomedical applications.
科研通智能强力驱动
Strongly Powered by AbleSci AI