提高小分子药物的活性和选择性  

On improving the activity and selectivity of small molecule drugs

作　　者：郭颖[1] 郭宗儒[1] GUO Ying;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》2023年第8期2016-2034,共19页Acta Pharmaceutica Sinica

摘　　要：小分子药物目前仍是治疗的主流,特异性治疗的生物药日益显示其优势,构成了对小分子药物创制和应用的挑战。小分子药物的优势是方便口服,患者依从性好。构建小分子药物的难点,是将药效、药代、选择性和安全性都融于化学结构之中。由于尺寸小,表面积不大,小分子药物就会对众多蛋白有不同程度的适配性结合,导致脱靶引起不良反应,在这个意义上选择性作用是首要的。在以靶标为核心构建和优化分子结构,又需要全盘顾及各个属性的要求,往往顾此失彼,达到全维度的优化实在勉为其难。本世纪的药物创制,广泛注入了分子生物学和结构生物学元素,涌现了新的策略和技术,并获得了成功,满足了患者的需求。例如共价结合药物,是在结构生物学指引下,将适度的“亲电弹头”连接在分子的恰当位置,在分子互补性的结合中,加以共价键不可逆锁定。分子生物学直接应用于抗体偶联药物(ADC)的研制中,抗体(A)作为载体和导向(药代),将毒性分子(D)传输到癌性细胞内,发挥杀伤作用(药效)。隔离的药效和药代分子实体靠连接基偶联(C)成ADC分子。PROTAC也是双功能分子,招募靶蛋白和泛素连接酶E3,形成三元复合物,犹如催化剂,使靶蛋白发生泛素化,导致被蛋白酶体降解。此外,近年来药物固定的配伍应用,在提高选择性、安全性、长效性和治疗效果方面也有长足进步,可视作不拘一格的物理合用的创新策略。本文列举一些成功实例,从药物化学和治疗应用的视角,简要讨论上述内容。Although small molecule drugs(SMD)are still mainstream for the treatment of diseases,large molecule biologicss of many advantages,pose a challenge to the further discovery and use of SMD.The advantages of SMD are the convenience of oral administration and good patient compliance.However,the challenge with SMD is to integrate the PD,PK,selectivity and safety into a chemical structure.Because of their small size and surface area they often bind to various proteins,and off-target actions can cause adverse reactions.In this sense,selectivity is critical.Based upon target as the core to construct a chemical structure,it is necessary to consider the requirements of all the attributes,but achievement of the full-dimensional optimization is difficult.Modern drug discovery has been greatly enhanced by molecular biology and structural biology,and new strategies and technologies have emerged,which have created many successful medicines.For example,under the guidance of structural biology,covalent binding drugs connect moderate"electrophilic warheads"to the appropriate positions of molecules,and upon binding to their targets the electrophiles are irreversibly linked to the target by covalent bonds.Molecular biology can be directly applied to the development of antibody-coupled drugs(ADC).The antibody(A)acts as a carrier and a guide(for PK),and carries toxic molecules(D)into cancer cells,thus playing a killing role(for PD).The separate pharmacodynamic and pharmacokinetic entities are coupled(C)by linkers.PROTACs are also bifunctional molecules,which recruit a target protein and ubiquitin ligase E3 to form a ternary complex,which then acts as a catalyst to ubiquitinate the target protein and lead to degradation by the proteasome.In addition,in recent years,the combination of two fixed-dose drugs has improved selectivity,safety,and longterm benefit with many severe diseases,and can be regarded as an innovative strategy of physical combination.This review discusses some successful examples to briefly present the principles from

关 键 词：选择性 共价结合药物 抗体偶联药物 PROTAC 药物组合 

分 类 号：R914[医药卫生—药物化学]