Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking
Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC–MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the “one-pot” discovery of prototype drugs and their metabolites...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | Acta Pharmaceutica Sinica B |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383525002199 |
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| author | Haodong Zhu Xupeng Tong Qi Wang Aijing Li Zubao Wu Qiqi Wang Pei Lin Xinsheng Yao Liufang Hu Liangliang He Zhihong Yao |
| author_facet | Haodong Zhu Xupeng Tong Qi Wang Aijing Li Zubao Wu Qiqi Wang Pei Lin Xinsheng Yao Liufang Hu Liangliang He Zhihong Yao |
| author_sort | Haodong Zhu |
| collection | DOAJ |
| description | Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC–MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the “one-pot” discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS2 spectral similarity, incorporating innovations and improvements in feature degradation of MS2 spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS2 similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%–40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications. |
| format | Article |
| id | doaj-art-e751a94b7c8543a3836a7f4ee1d2054c |
| institution | OA Journals |
| issn | 2211-3835 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj-art-e751a94b7c8543a3836a7f4ee1d2054c2025-08-20T02:22:01ZengElsevierActa Pharmaceutica Sinica B2211-38352025-06-011563210322510.1016/j.apsb.2025.03.050Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networkingHaodong Zhu0Xupeng Tong1Qi Wang2Aijing Li3Zubao Wu4Qiqi Wang5Pei Lin6Xinsheng Yao7Liufang Hu8Liangliang He9Zhihong Yao10State Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; Guangxi Key Laboratory of Special Biomedicine; School of Medicine, Guangxi University, Nanning 530004, ChinaHangzhou Chenfeng Qingxing Technology Co., Ltd., Hangzhou 310000, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, ChinaState Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; College of Chemical Engineering, Xiangtan University, Xiangtan 411105, China; Corresponding authors.State Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; Corresponding authors.State Key Laboratory of Bioactive Molecules and Druggability Assessment; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education (MOE) of China; Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs; Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, College of Pharmacy, Jinan University, Guangzhou 510632, China; Corresponding authors.Effective annotation of in vivo drug metabolites using liquid chromatography-mass spectrometry (LC–MS) remains a formidable challenge. Herein, a metabolic reaction-based molecular networking (MRMN) strategy is introduced, which enables the “one-pot” discovery of prototype drugs and their metabolites. MRMN constructs networks by matching metabolic reactions and evaluating MS2 spectral similarity, incorporating innovations and improvements in feature degradation of MS2 spectra, exclusion of endogenous interference, and recognition of redundant nodes. A minimum 75% correlation between structural similarity and MS2 similarity of neighboring metabolites was ensured, mitigating false negatives due to spectral feature degradation. At least 79% of nodes, 49% of edges, and 97% of subnetworks were reduced by an exclusion strategy of endogenous ions compared to the Global Natural Products Social Molecular Networking (GNPS) platform. Furthermore, an approach of redundant ions identification was refined, achieving a 10%–40% recognition rate across different samples. The effectiveness of MRMN was validated through a single compound, plant extract, and mixtures of multiple plant extracts. Notably, MRMN is freely accessible online at https://yaolab.network, broadening its applications.http://www.sciencedirect.com/science/article/pii/S2211383525002199Drug metabolismMRMNLC–MSMS2 feature degradation improvementRedundant ions identificationEndogenous interference elimination |
| spellingShingle | Haodong Zhu Xupeng Tong Qi Wang Aijing Li Zubao Wu Qiqi Wang Pei Lin Xinsheng Yao Liufang Hu Liangliang He Zhihong Yao Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking Acta Pharmaceutica Sinica B Drug metabolism MRMN LC–MS MS2 feature degradation improvement Redundant ions identification Endogenous interference elimination |
| title | Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking |
| title_full | Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking |
| title_fullStr | Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking |
| title_full_unstemmed | Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking |
| title_short | Unveiling the metabolic fate of drugs through metabolic reaction-based molecular networking |
| title_sort | unveiling the metabolic fate of drugs through metabolic reaction based molecular networking |
| topic | Drug metabolism MRMN LC–MS MS2 feature degradation improvement Redundant ions identification Endogenous interference elimination |
| url | http://www.sciencedirect.com/science/article/pii/S2211383525002199 |
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