精准医学应用“组学”和系统生物学在分子水平上分析患者的病因,并以靶向治疗手段对患者做个体化处治。精准医学与药物密切相关。药物作为治疗手段和物质供给侧,在精准医学中主要体现两个方面:针对特定的靶标或机制进行新药研发;针对疾病的分子特征对患者做个体化治疗的临床应用。基于特定靶标研发新分子实体是实施精准医疗的前提与保障;而精准医疗的效果和发现的线索又反馈于新药深化研究,二者相互依存和促进。在精准医学的框架下,新药研究所涵盖的大都是熟知内容:靶标的发现与确证;靶标与适应证的关联(概念验证);先导物的发现与优化;临床前研究的药效、药代和不良反应与临床试验的关联;药品设计、产业化和药物经济学的精益化等。从分子水平的视角看,药物的疗效源于药物分子的特定原子或基团与生物大分子的互补性和在三维空间的相互结合,这些原子基团或片段的严格排布映射了与效应靶标的精确结合。靶标蛋白即使发生微小的残基改变,也会导致大分子的构象变化,这时药物的分子结构必须做精细的微调以适配变化了的结构(构象)要求以避免脱靶作用。为了进行个体化治疗,需要根据患者生物标示物的分子特征选择有针对性的药物,因而需要研制多种新分子实体。本文列举一些实例试图解析在精准医学时代药物分子设计的某些趋势。 Precise medical applications “group learning” and systems biology at the molecular level analysis of the patient’s etiology, and target-oriented treatment of patients with individualized treatment. Precision medicine and drugs are closely related. As the treatment method and material supply side, medicine mainly reflects two aspects in precision medicine: new drug research and development for specific target or mechanism; and clinical application of individualized treatment for patients according to molecular characteristics of disease. The development of new molecular entities based on specific targets is a prerequisite and guarantee for the implementation of precision medicine. The results of precision medicine and clues are also fed back to the deepening research of new drugs, which are interdependent and promoted. Under the framework of precision medicine, the new drug research covers most of the well-known content: the discovery and confirmation of the target; the association of the target and the indication (proof of concept); the discovery and optimization of the leader; the efficacy of the preclinical study And adverse reactions and clinical trials; drug design, industrialization and the lean pharmaceutical economy. From a molecular perspective, the efficacy of a drug stems from the complementarity of the specific atoms or groups of the drug molecule with the biological macromolecules and their interdependence in three-dimensional space. The strict arrangement of these atomic groups or fragments maps the interaction with the effect target The exact combination. Even minor changes in the target protein can lead to conformational changes in the macromolecule, where the molecular structure of the drug must be finely tuned to accommodate changing structural (conformational) requirements to avoid off-target effects. For individualized treatment, targeted drugs need to be selected based on the molecular characteristics of the patient’s biomarkers, thus requiring the development of a variety of new molecular entities. This article lists some examples of attempts to resolve some trends in the design of drug molecules in the era of precision medicine.