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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。在缺乏受体信息的情况下,以天然配体为出发点,在结构的变换和活性的变化中,逐渐演化出先导物,以及实施先导物的优化。理性药物设计不只限于计算机辅助的手段,构效关系可以在多层次上进行分析,化学结构、构象特征、功能基(药效团)分布、物化性质等,都可成为演绎和优化结构的依据。西咪替丁是理性药物设计的另一种典范,充分应用了药物化学原理,如同系律、电子等排原理、拼合原理等。首创性药物的可贵在于没有借鉴和参考下开辟了一个新的治疗领域,包括靶标的确证和药物的成功。也由于首创药物未能充分优化,存在不足之处,为后续研发的替丁留下了空间,在模拟中后来居上。
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 absence of receptor information, the natural ligands are used as a starting point to gradually evolve the precursors and to optimize the precursors in the structural transformation and activity changes. Rational drug design is not limited to computer-aided methods. The structure-activity relationship can be analyzed at multiple levels. The chemical structure, the conformational characteristics, the distribution of functional groups (pharmacophore) and physicochemical properties can be the basis for deducing and optimizing the structure. Cimetidine is another example of rational drug design, the full application of the principles of medicinal chemistry, as the law, the principle of electronic isosceles, flat principle. The pride of medicines is that without reference and reference, a new therapeutic area has been opened up, including the confirmation of the target and the success of the drug. Also due to the first drug failed to fully optimize, there are deficiencies, for the follow-up research and development left space, leaving behind in the simulation.