双功能分子设计刍议

A brief analysis of bifunctional molecules

药物的高选择性作用是扩大治疗窗避免不良反应的保障。从药物的分子结构视角考察当今的药物化学方法或技术,重点反映在提高选择性的策略和理念上。以靶标为核心的药物创制,为保障由体外对分子和细胞水平的活性化合物转化为对患者安全有效的药物,需要在空间和时间上精准地清除或抑制致病的有害靶标。为实现这种优化,在药物分子结构上要作多维度的考量和设计,把药物分子精确地输送到靶组织处,摧毁有害靶标。本文列举的双功能分子的药物研究,试图从药物化学层面浅作剖析。例如抗体药物偶联物,是利用抗体对抗原的特异性结合,将与之共价键连接的细胞毒性分子,带到肿瘤细胞作特异性杀伤。抗体的功能是导向性运载,细胞毒性分子的功能是对靶标的强力杀伤。基于靶标结构设计不可逆抑制剂,是在与靶标结合的基础上,在活性分子的结构中精确地引入亲电性适度的基团,形成第二个功能性基团,与靶标作共价键结合,经"二次打击"提高选择性。晚近发展的Hy T、PROTAC和d TAG等平台技术,是在结构上有双功能的化学特征,在机制上经化学募集,诱导蛋白-蛋白相互作用,最终裂解清除错误有害的蛋白靶标。尽管这类分子尺寸加大,宏观性质带来药代和物化性质的瓶颈,但由于高度选择性和广泛蛋白靶标的适用性,这些技术具有广阔的前景。

Selectivity of drug action is a determinant for wide therapeutic window and less adverse response.From the viewpoint of molecular structure the conception and strategy of drug design are mainly embodied in raising selectivity.For the target-based drug discovery it is crucial to precisely obliterate detrimental targets in dimension of time and space,so as to efficaciously translate the in vitro active compounds into in vivo therapeutic medicines.To realize this translation drug molecules must be accurately transported to and destroy the harmful targets.To this end,chemical structures of drugs must be manipulated in multiple dimensions.This article attempts to concisely describe several kinds of bifunctional molecules for raising selectivity from the standpoint of medicinal chemistry.The bifunctionality of antibody-drug conjugates（ADCs） involves in the guidance and carrier of the antibody to guide ADC and reach to target cells,and simultaneously injury quality of the toxin moiety of ADC interacts with and destroys targets.Based upon target 3 D structures design of irreversible inhibitors consist in connecting an appropriate electrophilic moiety to a well-defined ligand to endow the molecule with an additional ability to covalently bond to a specific amino acid residue.Hydrophobic tag（Hy T）,proteosis-targeting chimera（PROTAC）,and degradation tag（d TAG） are new developed technologies,which are structurally characterized by bifunctionality,and mechanistically these compounds are capable of recruiting protein of interest（POI）,inducing protein-protein interaction（PPI）,and cleaving POI.In spite of large molecular size and the bottleneck of pharmacokinetic and physicochemical properties these technologies still have broad development prospect owing to high selectivity and wide adaptations.