基于结构的理性设计:扎那米韦和奥塞米韦

发布时间：2018-11-11 14:34

【摘要】：新药创制是复杂的智力活动,涉及科学研究、技术创造、产品开发和医疗效果等多维科技活动。每个药物都有自身的研发轨迹,而构建化学结构是最重要的环节,因为它涵盖了药效、药代、安全性和生物药剂学等性质。本栏目以药物化学视角,对有代表性的药物的成功构建,加以剖析和解读。基于流感神经氨酸酶的晶体结构和生化研究,以底物的过渡态作为出发点,将分子模拟的结果指导抑制剂的设计,在设计合成的有限化合物中,诞生了首创的扎那米韦。然而也由于过分拘泥模仿底物的结构,过强的极性导致扎那米韦药代的缺陷和用药的局限性。奥塞米韦也是基于酶的三维结构和模拟底物过渡态,但注意到成药性的要求,也在为数不多的化合物中,成功地合成出结构简单而合理的口服抗流感药。从研发和上市的顺序看,奥塞米韦是后继药物,但超越了首创的扎那米韦。
[Abstract]:New drug creation is a complex intellectual activity involving multi-dimensional scientific and technological activities such as scientific research, technological creation, product development and medical effects. Each drug has its own R & D track, and the construction of chemical structures is the most important step because it covers pharmacodynamics, pharmacology, safety and biopharmaceutical properties. This column analyzes and interprets the successful construction of representative drugs from the perspective of drug chemistry. Based on the crystal structure and biochemical study of influenza neuraminidase and taking the transition state of substrate as the starting point, the results of molecular simulation were used to guide the design of inhibitors. Among the limited compounds designed and synthesized, the first zanamivir was born. However, due to excessive restraint and imitation of substrate structure, excessive polarity leads to zanamivir defects and drug limitations. Ox is also based on the three-dimensional structure of enzymes and mimic the substrate transition state, but noted the requirements of drug formation, but also in a few compounds, successfully synthesized a simple and reasonable structure of oral antiinfluenza drugs. In the order of R & D and marketing, Osevir is a successor, but surpasses the first Zanamivir.
【作者单位】：中国医学科学院北京协和医学院药物研究所;
【分类号】：R91

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