基于结构设计的蛋白酶抑制剂沙奎那韦、安普那韦和地瑞那韦
发布时间：2018-08-07 18:00
【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。20世纪90年代在基于靶标结构设计药物(SBDD)的研究中,沙奎那韦是为数不多成功的一个。由于解析了HIV蛋白酶的作用机制和酶的三维结构,研究者得以从最简单的基本单元入手,在成药性理念的指导下,"生长"成与活性中心的形状、尺寸和电性呈互补结合的拟肽链,同时"注入"过渡态的类似结构,完成了首创的高活性的口服抗艾滋病药物沙奎那韦。进而研发者针对该首创药物的不足,继续在结构生物学的指引下,研制成活性更强、药代完善和克服耐药的两个更新产品。安普那韦和地瑞那韦在同一理念下研制成功,但无论在宏观生物学和化学性质上,还是微观的结合特征和热力学的焓-熵转化方面,都更胜一筹。
[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 pharmacochemistry. In the 1990s, in the research of drug design based on target structure, Zaquinavir is one of the few successful drugs. By analyzing the mechanism of HIV protease and the three-dimensional structure of the enzyme, the researchers were able to start with the simplest basic unit and, guided by the idea of drug formation, "grow" and shape the active center. Size and electrical properties of the complementary binding peptide chain, at the same time "injection" of the transition state of similar structures, completed the first highly active oral anti-AIDS drug Zaquinavir. In order to overcome the shortage of the original drug, the researchers continue to develop two new products with stronger activity, better pharmacokinetics and better drug resistance under the guidance of structural biology. Amponavir and denavir have been successfully developed under the same concept, but they are superior in macroscopic biological and chemical properties, microcosmic combination characteristics and enthalpy entropy transformation of thermodynamics.
【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
本文编号：2170876
[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 pharmacochemistry. In the 1990s, in the research of drug design based on target structure, Zaquinavir is one of the few successful drugs. By analyzing the mechanism of HIV protease and the three-dimensional structure of the enzyme, the researchers were able to start with the simplest basic unit and, guided by the idea of drug formation, "grow" and shape the active center. Size and electrical properties of the complementary binding peptide chain, at the same time "injection" of the transition state of similar structures, completed the first highly active oral anti-AIDS drug Zaquinavir. In order to overcome the shortage of the original drug, the researchers continue to develop two new products with stronger activity, better pharmacokinetics and better drug resistance under the guidance of structural biology. Amponavir and denavir have been successfully developed under the same concept, but they are superior in macroscopic biological and chemical properties, microcosmic combination characteristics and enthalpy entropy transformation of thermodynamics.
【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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