大环小分子药物

含有大环结构的小分子药物是近20年来药物化学关注的领域,是因为在提高药理活性和选择性,完善成药性上显示出一定的优势,大环结构兼顾了与靶标结合的微观结构和药代动力学所需求的宏观性质。大环药物源自于天然活性物质,近年来成功设计合成的大环药物扩大了传统小分子的化学空间,在一定程度上突破了熟知的类药5规则。大环分子也为研制可药性差的靶标和干预蛋白-蛋白相互作用的药物开辟了新的路径。本文以成功的实例着重阐述基于靶标结构的大环药物的分子设计,也讨论了天然大环药物的结构优化,同时对钉固肽的药物化学作了简要的叙述。

On the macrocyclic drugs

Small molecular drugs with large ring structure have recently attracted the attention in medicinal chemistry,the reason is their advantages in improving pharmacological activity and selectivity,and in satisfying drug-like properties.The macrocyclic structure takes into account both the microscopic structure for binding to targets and the macroscopic properties required by the pharmacokinetics.Although macrocyclic drugs historically originated from natural products,in recent years,they have been successfully designed,expanded the chemical space of traditional small molecules,and,to some extent,broken through the well-known the Role of Five in drug innovation.In addition,macrocyclic molecules also pave the path for developing drugs for non-druggability targets and for interfering with protein-protein interaction.This article focuses on the molecular design of macrocyclic drugs with some successful examples,concisely discusses structural optimization of a few macrocyclic natural drugs,and briefly describes stapled peptides in medicinal chemistry.