中药药理与临床

复杂疾病具有多基因扰动、多通路失衡、动态演变等特点，而现代新药研发长期沿用还原论“单成分单靶点”药物发现范式（TDD），致使单靶点药物普遍存在应答率低、耐药频发、疗效局限等问题，在肿瘤、神经退行性疾病、代谢病等复杂慢病领域存在显著应用局限性。当前“具有多靶向系统性调节和干预功能的药物研发”成为科技创新的重要风向标，“单成分多靶点”药物发现范式（MTDD）已经成为全球药物研发的重要方向。传统中药复方以君臣佐使配伍理论为核心，历经数千年临床验证，依靠多成分协同、网络调控实现对疾病失衡网络的整体性干预，契合复杂疾病的治疗逻辑，蕴藏着古老的多靶点药物发现思想。国家药监局《中药注册分类及申报资料要求》（2021年实施）、《中药注册管理专门规定》（2023年实施），明确规定中药复方制剂属于中药创新药1.1类，为在中医药理论指导下的中药复方新药研制奠定了法律基础和优先地位。本文基于传统中医方剂理论的价值重估与多靶点药物原创范式构建的现实需求，提出中药复方新药发现（TCMCFDD）作为“多成分多靶点”药物发现新范式的定义和内涵：（1）以君臣佐使层级配伍规则，构建多成分协同制衡的科学体系，填补多药组合无系统理论的空白；（2）以临床人用经验和历史使用证据前置的逆向研发模式，大幅降低新药研发风险与试错成本；（3）以整体稳态调衡思维替代局部单点干预，解决单靶点无法系统性根除病变机制的短板。TCMCFDD本质是对中医药传统组方智慧的系统性再审视与现代化范式重构，是衔接传统方剂配伍理论与现代新药研发科学的核心对话载体。该范式以君臣佐使、七情配伍等经典中医理论为底层逻辑，立足千年临床配伍经验，融合现代科学认识和多领域技术，突破现有MTDD研发范式的局限，实现传统方剂经验的科学化转译。本文梳理传统复方作为古代多靶点思想的内核，通过对中医方剂理论再认识、现代科学再诠释与科学范式再创新，系统阐释TCMCFDD的理论框架、范式创新、关键技术体系、现实挑战与发展路径。TCMCFDD作为我国本土具有代表性的新药发现理论与技术体系，突破现代还原论药学体系的认知局限与技术束缚，构建理论可阐释、机制可量化、过程可控制、成果可转化的原创完整新药发现链条，对于推动传统中医药经验从模糊、定性的临床实践，到标准化、证据化、可转化的现代药物研发体系，推动传统方剂升级为标准化、可复现、可产业化的现代制剂和先进制剂，打通传统临床经验与现代多药理学之间的理论鸿沟具有重要意义。

Complex diseases are characterized by polygenic perturbations， multi-pathway dysregulation and dynamic progression. However， modern new-drug research and development has long adopted the reductionist “single-component， single-target” drug discovery paradigm (TDD). This results in single-target drugs commonly suffering from low response rates， frequent drug resistance and limited therapeutic efficacy， presenting substantial practical limitations in complex chronic diseases such as cancers， neurodegenerative disorders and metabolic diseases.At present， drug development featuring multi‑targeted systemic regulation and intervention has emerged as a vital trend in scientific and technological innovation. The “single-component， multi-target” drug discovery paradigm (MTDD) has become a major direction for global pharmaceutical R&D.Traditional Chinese herbal formulas are centered on the compatibility theory of sovereign-minister-assistant-guide. Having undergone thousands of years of clinical validation， they exert holistic intervention on diseased dysregulated networks via multi‑component synergy and network regulation. This conforms to the therapeutic logic for complex diseases and embodies ancient ideas of multi-target drug discovery. Issued by the National Medical Products Administration (NMPA)， the Requirements for Classification and Application Dossiers of Traditional Chinese Medicine Registration (implemented in 2021) and the Special Provisions for the Administration of Traditional Chinese Medicine Registration (implemented in 2023) explicitly classify novel TCM compound preparations as Class 1.1 innovative TCM drugs. These regulatory provisions establish a solid legal basis and prioritize the research and development of innovative TCM compound formulations developed under the guidance of traditional Chinese medicine theories.Based on the re-evaluation of the value of traditional Chinese medicine formula theory and the practical demand for constructing an original multi-target drug discovery paradigm， this study proposes the definition and connotation of the TCM Compound-Formula-derived Drug Discovery(TCMCFDD) as a novel "multi-component and multi-target" drug discovery paradigm: (1) To construct a scientific system for the synergistic balance of multiple components based on the hierarchical compatibility principle of sovereign， minister， assistant and guide， filling the theoretical gap in the systematic guidance of multi-drug combination research; (2) To adopt a reverse research and development model with prior clinical human application experience and historical medication evidence， which substantially reduces the R&D risks and trial-and-error costs of new drugs; (3) To replace localized single-point intervention with the holistic thinking of homeostasis regulation， overcoming the inherent limitation of single-target strategies that fail to fundamentally eliminate pathological mechanisms in a systematic manner.TCMCFDD is neither a simple inheritance of empirical ancient formulas nor a mechanical reproduction of traditional compatibility systems. Nor does it partially tailor traditional theories within the framework of modern pharmacology. Instead， it represents a systematic re-examination of the classical formula wisdom of traditional Chinese medicine and a modernized paradigm reconstruction， serving as a core translational carrier that bridges traditional compatibility theories and modern scientific new drug research and development.Guided by classical traditional Chinese medicine theories including sovereign-minister-assistant-guide compatibility and seven-emotion compatibility as its underlying logic， this paradigm draws on millennia-long clinical compatibility experience and integrates systems biology， multi-omics， artificial intelligence and modern pharmaceutical technologies. It overcomes the limitations of the current MTDD research paradigm and achieves the scientific translation of empirical experience of traditional Chinese herbal formulas.This study sorts out the core connotation of traditional herbal formulas as the ancient embodiment of multi-target therapeutic concepts. Through the re-understanding of TCM formula theories， the re-interpretation of modern scientific evidence， and the re-innovation of scientific paradigms， this paper systematically elaborates the theoretical framework， paradigm innovation， key technical system， practical challenges and development paths of TCMCFDD. As a representative indigenous theoretical and technical system for new drug discovery in China， TCMCFDD breaks the cognitive and technical constraints of the modern reductionist pharmaceutical system. It constructs an original and complete new drug discovery chain featuring interpretable theories， quantifiable mechanisms， controllable processes and transformable achievements. Importantly， TCMCFDD facilitates the transformation of traditional TCM experience from ambiguous and qualitative clinical practice to a standardized， evidence-based and translatable modern drug R&D system. It promotes the upgrading of traditional formulas into standardized， reproducible and industrializable modern and advanced preparations， and bridges the theoretical gap between traditional clinical experience and modern multi-pharmacology. With the continuous improvement of theoretical systems， intelligent technologies and international evaluation criteria， TCMCFDD will further lead the innovation and reform of novel drug research and development for complex diseases， providing a China-originated original scientific solution for the global development of multi-target drugs.