药物化学视角的双功能分子  

Bifunctional molecules from viewpoint of medicinal chemistry

作　　者：郭宗儒[1] GUO Zong-ru(Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,北京100050

出　　处：《药学学报》2024年第10期2677-2696,共20页Acta Pharmaceutica Sinica

摘　　要：小分子药物包含有多维属性,新药创制须满足安全性、有效性、稳定性、可控性和患者顺应性等要求。这些属性可概括为药理活性和成药性,都隐含在药物的化学结构之中。药理活性和不良反应是药物分子与向靶(ontarget)或脱靶(off-target)蛋白分子间相互作用,产生的活性(毒性)强度和选择性是由药物的微观结构所决定。药代动力学和物理化学性质是由药物的宏观性质所决定,微观结构与宏观性质交织融合在分子结构之中。构建双功能分子是实现“微观结构与宏观性质统一”的一个途径,是从结构上理顺药效-药代、药效-不良反应(选择性)关系的策略和方法。本文以成功上市或处于临床研究的药物为例,对抗体偶联药物、蛋白靶向降解嵌合体、分子胶、多肽修饰等行之有效的技术方法从药物化学视角诠释双功能分子的结构特征。此外,笔者将共价键结合药物和过渡态类似物以及前药也归纳到双功能分子范畴,强调在分子设计和结构优化中功能基团双功能性的区分和重要意义。Small molecule drugs comprise multi-dimensional features,and drug creation has to meet requirements such as safety,effectiveness,stability,controllability,and patient compliance.These attributes can be summarized as pharmacological activity and druglikeness,which are implicit in the chemical structure of the drug.Pharmacological activity and adverse reactions are caused by the interaction between drug molecules and on-target or off-target protein.The microstructure of the drug determines the activity/toxicity intensity and selectivity.Pharmacokinetic and physicochemical properties are related to the macroscopic properties of the drug,and the microstructure and macroscopic properties are intertwined and integrated into the molecular structure.Conception and construction of bifunctional molecules are one of routes to achieve"unification of micro and macro"and structurally straighten out the relationship between pharmacodynamics-pharmacokinetics,drug efficacy-adverse reactions(selectivity).This article takes drugs that have been successfully marketed or under clinical trials as examples to explain the structural characteristics of bifunctional molecules from the viewpoint of medicinal chemistry.The productive technical methods include antibody-drug conjugate,proteolysis-targeting chimeras,molecular glues,peptide modifications,and so on.In addition,this overview also classifies covalently binding drugs,transition-state analogs,and prodrugs into the category of bifunctional molecules,emphasizing the importance of bifunctional groups in molecular design and structure optimization.

关 键 词：双功能分子 抗体偶联药物 蛋白靶向降解嵌合体 分子胶 共价键药物 过渡态类似物 前药 

分 类 号：R914[医药卫生—药物化学]