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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。
The creation of new drugs 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 development trajectory, and the construction of the chemical structure is the most important part, because it covers the properties such as efficacy, drug substitution, safety and biopharmaceutical. This column from the perspective of medicinal chemistry, representative of the successful construction of drugs, to be analyzed and interpreted. In the 1990s, saquinavir was one of the few successes in the design of a drug based on target structure design (SBDD). Due to the analysis of the mechanism of action of HIV protease and the three-dimensional structure of the enzyme, the researcher can start from the simplest basic unit, under the guidance of the concept of medicine, the shape, size and electrical activity of the “growth” Complementation of the peptidomimetic chain, and at the same time a similar structure of the transition state of “injection” completes the first highly active oral anti-AIDS drug saquinavir. Furthermore, the developers, in response to the deficiency of the first-of-its-kind drug, continue to develop two newer products that are more active, complete with drug substitution and overcome drug resistance under the guidance of structural biology. Amprenavir and darunavir have been successfully developed under the same philosophy, but are superior in both macroscopical and chemical properties, microscopic binding characteristics and enthalpy-entropy transformation in thermodynamics.