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。 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. Based on the crystal structure and biochemical studies of influenza neuraminidase, the substrate transition state is taken as the starting point. The molecular simulation results guide the design of the inhibitor. Zanamivir, the first of its kind, was designed and synthesized. However, too rigidly imitate the structure of the substrate, too strong polarity leads to defects in the pharmacokinetics of zanamivir and limitations of medication. Oseltamivir is also based on the enzymatic three-dimensional structure and the simulated substrate transition state. However, taking into account the need for drug-induced properties, oseltamivir has also succeeded in synthesizing a simple and rational oral anti-influenza drug among a few compounds. Seen from the order of research and development and listing, oseltamivir is a successor drug, but beyond the first of zanamivir.