药学学报, 2022, 57(2): 251-264
引用本文:
郭宗儒*. 药物化学视角的新药创制[J]. 药学学报, 2022, 57(2): 251-264.
GUO Zong-ru*. Drug discovery from viewpoint of medicinal chemists[J]. Acta Pharmaceutica Sinica, 2022, 57(2): 251-264.

药物化学视角的新药创制
郭宗儒*
中国医学科学院、北京协和医学院药物研究所, 北京 100050
摘要:
以患者需求为核心,实现临床价值为导向,是新药创制的宗旨和路径。无论首创性药物或是仿创性药物都是为了满足患者对无药可治或更加安全有效的药物需求。以生物学基础研究驱动的创新药物,为实现临床价值包含三个要素或环节,即理解致病的分子机制;把握疾病的微观特征;阐明药物的作用机制。这三者之间的相互关联,是贯穿其中的转化医学,药物化学扮演重要角色。即将生物学/医学的基础研究成果通过各种模型阐明疾病发生发展的分子机制,从分析分子调控过程中找到治疗疾病的关键节点。患者的症状、生化常规和影像特征等宏观表象,难以在分子水平上为药物分子设计提供信息,生物学的发展,得以在微观水平作分子生物学分析,例如基因缺失与变异、蛋白质组学、表观遗传学等技术,结合疾病的分子机制,可从多样本和大数据分析中归纳基因-蛋白(酶、受体、通道、信号分子等)与疾病的关系,对创制新药和疗法提供新的科学依据。洞察疾病的微观特征是上述发病的分子机制的延续和深化,为创制新药提供可行的科学路径。当阐明了疾病的分子机制和药物的作用机制,对既有药物(或活性物质)的应用就有了更深刻和广泛的认识,提供了药物设计和应用的新思路。构建新分子结构(NME)的药物化学是其中的重要环节,要求药物化学研究者扩展固有的靶标-设计-合成-评价的模式,从大视野的角度,上溯关注基础研究及其成果,及时向创制新药的方向转轨;向下游关注临床要求,结合疾病的微观特征,落实转化过程的具体内容,这对于首创性药物的研发是非常关键的步骤。本文从药物化学视角浅谈一些看法。
关键词:    药物创制      临床价值      转化医学      分子机制      药物设计     
Drug discovery from viewpoint of medicinal chemists
GUO Zong-ru*
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Taking patient needs as the core and realizing clinical value as the guidance are the purpose and path of drug discovery. Whether the first-in-class drug or follow-on drugs are all to meet the demands of patients for drugs that are not treatable or more safe and effective. In order to realize clinical value, innovative drugs driven by basic biological research include three elements:understanding the molecular mechanism of pathogenesis; Grasping the microscopic features of the disease; clarifying the mechanism of action of drugs. The interrelation among the three is the translational medicine, and the medicinal chemistry plays an important role in the translations. That is, based on the results of basic research in biology/medicine, knowledge of the molecular mechanism of disease depends upon the establishment of various in vitro/in vivo models to find the key node and molecular regulation for the treatment of disease. Combined with the knowledge of gene deletion and variation, proteomics, epigenetics and other technologies, the molecular mechanism of disease provides multi-molecular information on the level of gene, proteins, enzymes, receptors, ion channels and signal transduction for molecular drug design. Insight into the microscopic characteristics of diseases would deepen the understanding of the molecular mechanism of the pathogenesis, as well as provide a feasible scientific path for the creation of new drugs. When the molecular mechanism of disease and the action mechanism of drugs are clarified, we have a deeper and wider understanding of the application of existing drugs (or active compounds), and may offer new ideas for drug design and application. In this translational process the medicinal chemistry plays a key role which requires medicinal chemists to break through the habitual thinking and working mode, backtracking (upstream) to basic research and its achievements and applying to the direction of creating new drugs in time, as well as paying attention to the clinical requirements (downstream) and implementing the specific content of the transformation process for the R&D of innovative drugs.
Key words:    drug discovery    clinic value    translation medicine    molecular mechanism    drug design   
收稿日期: 2021-12-13
DOI: 10.16438/j.0513-4870.2021-1784
通讯作者: 郭宗儒,E-mail:zrguo@imm.ac.cn
Email: zrguo@imm.ac.cn
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