基于疾病演变分子轨迹发现中药作用靶标及先导化合物思路探讨  

Discovery of the targets and lead compounds of traditional Chinese medicine based on the molecular trajectory of diabetes evolution

作　　者：张瑜[1] 龙江兰 王爱婷 吕昊 邓科君[2] 林昊[2] 鄢丹 ZHANG Yu;LONG Jiang-lan;WANG Ai-ting;LÜHao;DENG Ke-jun;LIN Hao;YAN Dan(Beijing Institute of Clinical Pharmacy,Beijing Friendship Hospital,Capital Medical University,Beijing 100050,China;School of Life Science and Technology,University of Electronic Science and Technology of China,Chengdu 610054,China)

机构地区：[1]首都医科大学附属北京友谊医院,北京市临床药学研究所,北京100050 [2]电子科技大学生命科学与技术学院,四川成都610054

出　　处：《药学学报》2024年第8期2199-2204,共6页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金项目(82130112,82204699);青年北京学者项目(2022-051);国家中医药管理局高水平中医药重点学科建设项目(zyyzdxk-2023003)。

摘　　要：探索中药作用靶标(群)是推动中药创新发展的重要命题,但囿于“是否与疗效相关、与疾病相关”而备受关注。项目组前期通过临床研究发现,糖尿病发生发展中的代谢组特征分子,与玉泉丸疗效应答显著相关。以此为线索,拟拓展糖尿病发生发展的多组学特征信息,发现玉泉丸降糖关键作用靶标(群)及其先导化合物。包括:(1)从临床切入,运用融入生成式人工智能的组学技术,挖掘蛋白质组、微生物组特征信息,连同代谢组特征分子整合形成驱动因素,刻画糖尿病演变分子轨迹及其经玉泉丸治疗后的转归;(2)以演变分子轨迹为纽带与指针,运用拟人源化模型和化学蛋白质组等分子生物学技术,发现玉泉丸降糖关键作用靶标(群),配以前瞻性临床样本验证;(3)利用图神经网络技术建立关键作用靶标(群)整体评判方法,探寻临床病证明确、作用机制清晰的药源性/内源性先导化合物,为关联临床疗效的中药复杂活性成分作用靶标(群)与创新药物的发现提供新范式、新技术。Exploring the action targets(groups)of traditional Chinese medicine(TCM)is an important proposition to promote the innovation and development of TCM,but it has attracted a lot of attention as to whether it is related to the efficacy or the disease.Our team found that the metabolomic signature molecules in the development of diabetes mellitus(DM)were significantly associated with the clinical efficacy of Yuquan Pill through a large clinical sample study.Taking this as a clue,our team intends to expand the information on the omics features of DM development,and discover the key targets(groups)and their lead compounds for the hypoglycemic effect of Yuquan Pill.The project includes:①Based on the retrospective clinical trials,using omics technology integrated with generative artificial intelligence,mining the characteristic information of proteome and microbiome,forming driving factors together with metabolome characteristic molecules,and characterizing the molecular trajectories of diabetes evolution and their interference by Yuquan Pill;②Taking the evolving molecular trajectories as a link and pointer,using anthropomorphic modeling and molecular biology techniques such as chemical proteomics to discover the key targets(groups)of Yuquan Pill's hypoglycemic effect,with the prospective clinical samples for validation;③Evaluate the overall response of key targets(groups)using graph neural network technology,and search for drug-derived/endogenous lead compounds with proven clinical pathologies and clear mechanisms of action,so as to provide a new paradigm and technology for the discovery of complex active ingredient targets(groups)of TCM that are related to their clinical efficacy,as well as for the discovery of innovative medicines.

关 键 词：关联临床 糖尿病演变分子轨迹 作用靶标 先导化合物 玉泉丸 

分 类 号：R917[医药卫生—药物分析学]