{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T05:18:40Z","timestamp":1783487920746,"version":"3.55.0"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T00:00:00Z","timestamp":1783468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Biosci."],"abstract":"<jats:p>Traditional Chinese Medicine constitutes a chemically diverse and pharmacologically rich reservoir of bioactive compounds, often exhibiting multi-target pharmacological properties that are potentially valuable for complex metabolic disorders such as type 2 diabetes mellitus (T2DM). However, systematic prioritization of active and safe constituents remains challenging, as therapeutic efficacy must be optimized concurrently with toxicity risk. Here, we present a safety-aware Multi-Task Graph Attention Network (SM-GAT) framework that jointly models anti-diabetic efficacy and toxicity liabilities of TCM-derived compounds within a unified architecture. Four tasks are simultaneously optimized: inhibition of dipeptidyl peptidase-4 (DPP4), inhibition of \u03b1-glucosidase, acute oral toxicity, and clinically relevant toxicity. By enabling shared molecular representation learning across heterogeneous yet biologically related endpoints, SM-GAT facilitates knowledge transfer between efficacy and safety domains. Across all prediction tasks, SM-GAT achieved competitive or superior performance compared with single-task graph neural networks and other baseline models, achieving ROC-AUC values up to 0.892 for \u03b1-glucosidase inhibition. Notably, multi-task learning yields pronounced improvements in data-limited settings, highlighting effective cross-task regularization. Large-scale virtual screening of the TCMBank library demonstrates practical applicability, enabling efficient prioritization of structurally diverse candidates with favorable predicted efficacy\u2013safety balance. Several structurally diverse lead compounds, including ellagic acid derivatives, are identified with favorable predicted efficacy\u2013safety balance. Furthermore, atom-level attention analysis highlighted chemically interpretable substructures associated with predicted efficacy and toxicity-related molecular representations. Collectively, this study establishes an interpretable multi-objective framework for safety-aware lead discovery, providing a computational framework for integrating traditional botanical resources into anti-diabetic lead discovery.<\/jats:p>","DOI":"10.3389\/fmolb.2026.1854162","type":"journal-article","created":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:53:43Z","timestamp":1783486423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SM-GAT: a safety-aware multi-task graph attention network for multi-target anti-diabetic lead discovery from natural products"],"prefix":"10.3389","volume":"13","author":[{"given":"Jianxin","family":"Zhang","sequence":"first","affiliation":[{"name":"The Second Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Clinical School of Medicine, Yunnan University of Traditional Chinese Medicine","place":["Kunming, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengnan","family":"Guo","sequence":"additional","affiliation":[{"name":"The Second Qilu Hospital of Shandong University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1837","DOI":"10.1007\/s40200-021-00853-9","article-title":"Potential antidiabetic phytochemicals in plant roots: a review of in vivo studies","volume":"20","author":"Ardalani","year":"2021","journal-title":"J. Diabetes Metabolic Disorders"},{"key":"B2","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1515\/znc-2024-0192","article-title":"Antidiabetic phytochemicals: an overview of medicinal plants and their bioactive compounds in diabetes mellitus treatment","volume":"80","author":"Ashagrie","year":"2025","journal-title":"Zeitschrift fur Naturforschung. C, J. Biosci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e151581","DOI":"10.5812\/ijpr-151581","article-title":"Dipeptidyl Peptidase-4 inhibitors: a systematic review of structure-activity relationship studies","volume":"23","author":"Bayanati","year":"2024","journal-title":"Iran. Journal Pharmaceutical Research IJPR"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1901","DOI":"10.3390\/jox14040101","article-title":"Overview of computational toxicology methods applied in drug and green chemical discovery","volume":"14","author":"Bueso-Bordils","year":"2024","journal-title":"J. Xenobiotics"},{"key":"B5","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/j.fct.2007.09.092","article-title":"Safety assessment of sandalwood oil (Santalum album L.)","volume":"46","author":"Burdock","year":"2008","journal-title":"Food Chemical Toxicology An International Journal Published Br. Industrial Biol. Res. Assoc."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0310770","DOI":"10.1371\/journal.pone.0310770","article-title":"Chemical profiling and cytotoxicity screening of agarwood essential oil Aquilaria sinensis in brine shrimp nauplii and cancer cell lines","volume":"19","author":"Chan","year":"2024","journal-title":"PloS One"},{"key":"B7","doi-asserted-by":"publisher","first-page":"4566","DOI":"10.3390\/molecules26154566","article-title":"Inhibitory activity and mechanism investigation of hypericin as a novel \u03b1-Glucosidase inhibitor","volume":"26","author":"Dong","year":"2021","journal-title":"Mol. Basel, Switz."},{"key":"B8","doi-asserted-by":"publisher","first-page":"198","DOI":"10.1016\/j.jtcms.2021.07.005","article-title":"Drug discovery from traditional Chinese herbal medicine using high content imaging technology","volume":"8","author":"Fu","year":"2021","journal-title":"J. Traditional Chin. Med. Sci."},{"key":"B9","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/jdi.12711","article-title":"Meta-analysis and critical review on the efficacy and safety of alpha-glucosidase inhibitors in Asian and Non-Asian populations","volume":"9","author":"Gao","year":"2018","journal-title":"J. Diabetes Investigation"},{"key":"B10","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1038\/nrd1470","article-title":"Can the pharmaceutical industry reduce attrition rates?","volume":"3","author":"Kola","year":"2004","journal-title":"Nat. Rev. Drug Discov."},{"key":"B11","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/s2213-8587(17)30186-9","article-title":"Type 2 diabetes in adolescents and young adults","volume":"6","author":"Lascar","year":"2018","journal-title":"Lancet. Diabetes and Endocrinology"},{"key":"B12","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1016\/j.jep.2018.03.029","article-title":"Pomegranate polyphenols and urolithin A inhibit \u03b1-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells","volume":"220","author":"Les","year":"2018","journal-title":"J. Ethnopharmacology"},{"key":"B13","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1016\/s1875-5364(13)60037-0","article-title":"Traditional Chinese medicine network pharmacology: theory, methodology and application","volume":"11","author":"Li","year":"2013","journal-title":"Chin. Journal Natural Medicines"},{"key":"B14","doi-asserted-by":"publisher","first-page":"7688","DOI":"10.1038\/s41598-024-82498-1","article-title":"Integrating transcriptomic data with a novel drug efficacy prediction model for TCM active compound discovery","volume":"15","author":"Li","year":"2025","journal-title":"Sci. Reports"},{"key":"B15","article-title":"Proceedings of the 25th international conference on artificial intelligence and statistics vol. 151","volume-title":"8906--8920 PMLR, Proceedings of Machine Learning Research","author":"Liu","year":"2022"},{"key":"B16","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/s41392-023-01339-1","article-title":"TCMBank-the largest TCM database provides deep learning-based Chinese-Western medicine exclusion prediction","volume":"8","author":"Lv","year":"","journal-title":"Signal Transduction Targeted Therapy"},{"key":"B17","doi-asserted-by":"publisher","first-page":"10684","DOI":"10.1039\/d3sc02139d","article-title":"TCMBank: bridges between the largest herbal medicines, chemical ingredients, target proteins, and associated diseases with intelligence text mining","volume":"14","author":"Lv","year":"","journal-title":"Chem. Science"},{"key":"B18","doi-asserted-by":"publisher","first-page":"D930","DOI":"10.1093\/nar\/gky1075","article-title":"ChEMBL: towards direct deposition of bioassay data","volume":"47","author":"Mendez","year":"2019","journal-title":"Nucleic Acids Research"},{"key":"B19","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1111\/jdi.12754","article-title":"Efficacy and safety of combination therapy with an \u03b1-glucosidase inhibitor and a dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: a systematic review with meta-analysis","volume":"9","author":"Min","year":"2018","journal-title":"J. Diabetes Investigation"},{"key":"B20","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1111\/jdi.13679","article-title":"Diversity of pathophysiology in type 2 diabetes shown by islet pathology","volume":"13","author":"Mizukami","year":"2022","journal-title":"J. Diabetes Investigation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1016\/j.peptides.2017.11.023","article-title":"Dipeptidyl peptidase inhibitor therapy in type 2 diabetes: control of the incretin axis and regulation of postprandial glucose and lipid metabolism","volume":"100","author":"Mulvihill","year":"2018","journal-title":"Peptides"},{"key":"B22","doi-asserted-by":"publisher","first-page":"117247","DOI":"10.1016\/j.jep.2023.117247","article-title":"Phthalides from the rhizome of ligusticum chuanxiong hort. Attenuate diabetic nephropathy in mice","volume":"319","author":"Qi","year":"2024","journal-title":"J. Ethnopharmacology"},{"key":"B23","doi-asserted-by":"publisher","first-page":"100621","DOI":"10.1016\/j.crmeth.2023.100621","article-title":"Molecular geometric deep learning","volume":"3","author":"Shen","year":"2023","journal-title":"Cell Reports Methods"},{"key":"B24","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1038\/s41586-024-07019-6","article-title":"Genetic drivers of heterogeneity in type 2 diabetes pathophysiology","volume":"627","author":"Suzuki","year":"2024","journal-title":"Nature"},{"key":"B25","doi-asserted-by":"publisher","first-page":"btae416","DOI":"10.1093\/bioinformatics\/btae416","article-title":"ADMET-AI: a machine learning ADMET platform for evaluation of large-scale chemical libraries","volume":"40","author":"Swanson","year":"2024","journal-title":"Bioinformatics"},{"key":"B26","doi-asserted-by":"publisher","first-page":"36989","DOI":"10.1039\/d1ra06799k","article-title":"New quinoxaline compounds as DPP-4 inhibitors and hypoglycemics: design, synthesis, computational and bio-distribution studies","volume":"11","author":"Syam","year":"2021","journal-title":"RSC Advances"},{"key":"B27","volume-title":"Graph Attention Networks","author":"Velickovic","year":"2017"},{"key":"B28","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1038\/s41586-023-06693-2","article-title":"Genetic risk converges on regulatory networks mediating early type 2 diabetes","volume":"624","author":"Walker","year":"2023","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1039\/c4fo00859f","article-title":"Angelica sinensis polysaccharide regulates glucose and lipid metabolism disorder in prediabetic and streptozotocin-induced diabetic mice through the elevation of glycogen levels and reduction of inflammatory factors","volume":"6","author":"Wang","year":"2015","journal-title":"Food and Function"},{"key":"B30","doi-asserted-by":"publisher","first-page":"835","DOI":"10.1007\/s11101-021-09765-1","article-title":"A review of the botany, traditional uses, phytochemistry and pharmacology of stemonae radix","volume":"21","author":"Wang","year":"2022","journal-title":"Phytochem. Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1303693","DOI":"10.3389\/fphar.2024.1303693","article-title":"A critical assessment of traditional Chinese medicine databases as a source for drug discovery","volume":"15","author":"Wang","year":"2024","journal-title":"Front. Pharmacology"},{"key":"B32","doi-asserted-by":"publisher","first-page":"475","DOI":"10.1038\/nrd4609","article-title":"An analysis of the attrition of drug candidates from four major pharmaceutical companies","volume":"14","author":"Waring","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"B33","doi-asserted-by":"publisher","first-page":"D1432","DOI":"10.1093\/nar\/gkac1074","article-title":"TOXRIC: a comprehensive database of toxicological data and benchmarks","volume":"51","author":"Wu","year":"2023","journal-title":"Nucleic Acids Research"},{"key":"B34","doi-asserted-by":"publisher","first-page":"3370","DOI":"10.1021\/acs.jcim.9b00237","article-title":"Analyzing learned molecular representations for property prediction","volume":"59","author":"Yang","year":"2019","journal-title":"J. Chem. Inf. Model."},{"key":"B35","doi-asserted-by":"publisher","first-page":"113216","DOI":"10.1016\/j.jep.2020.113216","article-title":"The anti-diabetic activity of licorice, a widely used Chinese herb","volume":"263","author":"Yang","year":"2020","journal-title":"J. Ethnopharmacology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s13020-024-01056-z","article-title":"Network pharmacology: a crucial approach in traditional Chinese medicine research","volume":"20","author":"Zhai","year":"2025","journal-title":"Chin. Medicine"},{"key":"B37","doi-asserted-by":"publisher","first-page":"bbaf533","DOI":"10.1093\/bib\/bbaf533","article-title":"Computational toxicology in drug discovery: applications of artificial intelligence in ADMET and toxicity prediction","volume":"26","author":"Zhang","year":"2025","journal-title":"Briefings Bioinformatics"},{"key":"B38","doi-asserted-by":"publisher","first-page":"103484","DOI":"10.1016\/j.jbi.2020.103484","article-title":"Multi-task learning models for predicting active compounds","volume":"108","author":"Zhao","year":"2020","journal-title":"J. Biomedical Informatics"},{"key":"B39","doi-asserted-by":"publisher","first-page":"896637","DOI":"10.3389\/fphar.2022.896637","article-title":"The angelica dahurica: a review of traditional uses, phytochemistry and pharmacology","volume":"13","author":"Zhao","year":"2022","journal-title":"Front. Pharmacology"},{"key":"B40","doi-asserted-by":"publisher","first-page":"btae304","DOI":"10.1093\/bioinformatics\/btae304","article-title":"Molecular property prediction based on graph structure learning","volume":"40","author":"Zhao","year":"2024","journal-title":"Bioinformatics"},{"key":"B41","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2040","DOI":"10.1080\/14786419.2023.2238113","article-title":"\u03b1-Glucosidase inhibitory activities of constituents from Psidium guajava leaves","volume":"38","author":"Zheng","year":"2024","journal-title":"Nat. Product Research"}],"container-title":["Frontiers in Molecular Biosciences"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1854162\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T04:54:00Z","timestamp":1783486440000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmolb.2026.1854162\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,8]]},"references-count":42,"alternative-id":["10.3389\/fmolb.2026.1854162"],"URL":"https:\/\/doi.org\/10.3389\/fmolb.2026.1854162","relation":{},"ISSN":["2296-889X"],"issn-type":[{"value":"2296-889X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,8]]},"article-number":"1854162"}}