{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T02:44:21Z","timestamp":1785725061547,"version":"3.56.0"},"reference-count":48,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["DUT25YG233"],"award-info":[{"award-number":["DUT25YG233"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Yunnan Talent Support Plan for Industrial Innovation Talents"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: Combining natural products with conventional antidiabetic agents to inhibit \u03b1-glucosidase activity is an effective strategy for preventing postprandial hyperglycemia. Baicalein, a natural flavonoid with well-documented low toxicity, showed potential synergistic effect with acarbose in diabetic models; however, the synergistic performance and mechanisms of the two agents targeting human maltase\u2013glucoamylase (MGAM) remain unclear. Methods: Recombinant human MGAM-C and MGAM-N were expressed in Pichia pastoris for in vitro inhibition assays. Maltose-loaded mice were used to assess the in vivo hypoglycemic activity and intestinal maltase inhibition. Inhibitor\u2013enzyme interactions were investigated by fluorescence spectroscopy, circular dichroism (CD), multiple molecular docking, and molecular dynamics (MD) simulations. Results: Baicalein potently inhibited MGAM-C and MGAM-N with IC50 values of 20.41 \u00b1 4.80 \u03bcM and 14.04 \u00b1 0.94 \u03bcM, respectively, and demonstrated a synergistic effect when combined with acarbose. In vivo, co-administration significantly reduced blood glucose levels and suppressed small intestinal maltase activity in maltose-loaded mice. Mechanistic studies revealed that baicalein functions as a non-competitive inhibitor by binding to the allosteric site of MGAM-C via stable hydrogen bonds with residues Ile1716 and Trp1749. This interaction induces conformational changes in the enzyme\u2019s secondary structure and optimizes the hydrophobic microenvironment of the active site, thereby enhancing the binding affinity and hydrogen bond stability of acarbose. These molecular events collectively contribute to the synergistic inhibition of MGAM-C hydrolytic activity. Conclusions: This research revealed the synergistic inhibitory effect of baicalein and acarbose on MGAM and the underlying mechanisms, thereby providing a theoretical basis for developing pharmaceutical formulations to enhance acarbose efficacy.<\/jats:p>","DOI":"10.3390\/ph19081215","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:43:27Z","timestamp":1785721407000},"page":"1215","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Unraveling the Synergistic Inhibition of Human Maltase\u2013Glucoamylase by Baicalein and Acarbose: Integrated Pharmacodynamics and Computational Insights"],"prefix":"10.3390","volume":"19","author":[{"given":"Xiaoshi","family":"He","sequence":"first","affiliation":[{"name":"School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Li","sequence":"additional","affiliation":[{"name":"Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyang","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Jiang","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5010-6426","authenticated-orcid":false,"given":"Yuesheng","family":"Dong","sequence":"additional","affiliation":[{"name":"School of Bioengineering, Dalian University of Technology, Dalian 116024, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,1]]},"reference":[{"key":"ref_1","unstructured":"Magliano, D.J., and Boyko, E.J. (2021). International Diabetes Federation\u00a9 IDF Diabetes Atlas. IDF Diabetes Atlas, International Diabetes Federation\u00a9 International Diabetes Federation."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"11925","DOI":"10.1080\/10408398.2022.2097637","article-title":"Dietary flavonoids prevent diabetes through epigenetic regulation: Advance and challenge","volume":"63","author":"Han","year":"2023","journal-title":"Crit. Rev. Food Sci. Nutr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"105824","DOI":"10.1016\/j.foodhyd.2020.105824","article-title":"Inhibitory mechanism of vitexin on \u03b1-glucosidase and its synergy with acarbose","volume":"105","author":"Ni","year":"2020","journal-title":"Food Hydrocoll."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejmech.2015.08.043","article-title":"Re-exploring promising \u03b1-glucosidase inhibitors for potential development into oral anti-diabetic drugs: Finding needle in the haystack","volume":"103","author":"Ghani","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9966750","DOI":"10.1155\/2022\/9966750","article-title":"Flavonols and flavones as potential anti-inflammatory, antioxidant, and antibacterial compounds","volume":"2022","author":"Chagas","year":"2022","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"133430","DOI":"10.1016\/j.foodchem.2022.133430","article-title":"FT-IR and FT-Raman fingerprints of flavonoids\u2014A review","volume":"393","author":"Krysa","year":"2022","journal-title":"Food Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"154458","DOI":"10.1016\/j.phymed.2022.154458","article-title":"Pharmacological properties of total flavonoids in Scutellaria baicalensis for the treatment of cardiovascular diseases","volume":"107","author":"Tan","year":"2022","journal-title":"Phytomedicine"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yang, J.L., Chen, M.Y., Zhang, W., Liu, J., Zhao, J., Ping, X., Lu, Y., He, P., and Pei, L. (2025). Integrated neurobehavioral and organ-specific safety profiling of baicalin: Acute\/subacute toxicity studies. Front. Pharmacol., 16.","DOI":"10.3389\/fphar.2025.1607919"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.jff.2017.08.005","article-title":"Baicalein improves insulin resistance via regulating SOCS3 and enhances the effect of acarbose on diabetes prevention","volume":"37","author":"Sun","year":"2017","journal-title":"J. Funct. Foods"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8319","DOI":"10.1021\/acs.jafc.7b02531","article-title":"Dietary flavonoids and acarbose synergistically inhibit \u03b1-glucosidase and lower postprandial blood glucose","volume":"65","author":"Zhang","year":"2017","journal-title":"J. Agric. Food Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1016\/j.jbiosc.2013.12.003","article-title":"Effect of Ca2+ on the activity and structure of \u03b1-glucosidase: Inhibition kinetics and molecular dynamics simulations","volume":"117","author":"Zhang","year":"2014","journal-title":"J. Biosci. Bioeng."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3929","DOI":"10.1016\/j.bmc.2011.05.033","article-title":"Mapping the intestinal alpha-glucogenic enzyme specificities of starch digesting maltase-glucoamylase and sucrase-isomaltase","volume":"19","author":"Jones","year":"2011","journal-title":"Bioorg. Med. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1007\/s13238-011-1105-3","article-title":"Structural insight into substrate specificity of human intestinal maltase-glucoamylase","volume":"2","author":"Ren","year":"2011","journal-title":"Protein Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"214","DOI":"10.2165\/00003495-198835030-00003","article-title":"Acarbose","volume":"35","author":"Clissold","year":"1988","journal-title":"Drugs"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"94","DOI":"10.2165\/00003088-199630020-00002","article-title":"Pharmacokinetic-Pharmacodynamic Relationships of Acarbose","volume":"30","author":"Salvatore","year":"1996","journal-title":"Clin. Pharmacokinet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4419","DOI":"10.1002\/jsfa.11795","article-title":"New glucogenesis inhibition model based on complete \u03b1-glucosidases from rat intestinal tissues validated with various types of natural and pharmaceutical inhibitors","volume":"102","author":"Kim","year":"2022","journal-title":"J. Sci. Food Agric."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8774","DOI":"10.1021\/acs.jafc.0c01668","article-title":"Dietary 5,6,7-trihydroxy-flavonoid aglycones and 1-deoxynojirimycin synergistically inhibit the recombinant maltase\u2013glucoamylase subunit of \u03b1-glucosidase and lower postprandial blood glucose","volume":"68","author":"Dong","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"146103","DOI":"10.1016\/j.ijbiomac.2025.146103","article-title":"The synergistic inhibition of isoginkgetin with miglitol and acarbose on \u03b1-glucosidase: Dynamics enzyme changes tracking","volume":"321","author":"Li","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"129056","DOI":"10.1016\/j.foodchem.2021.129056","article-title":"Comparative study of inhibition mechanisms of structurally different flavonoid compounds on \u03b1-glucosidase and synergistic effect with acarbose","volume":"347","author":"Yang","year":"2021","journal-title":"Food Chem."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lakowicz, J. (2006). Principles of Fluorescence Spectroscopy, Springer.","DOI":"10.1007\/978-0-387-46312-4"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"135327","DOI":"10.1016\/j.foodchem.2022.135327","article-title":"Soluble dietary fibres decrease \u03b1-glucosidase inhibition of epigallocatechin gallate through affecting polyphenol-enzyme binding interactions","volume":"409","author":"Li","year":"2023","journal-title":"Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"117213","DOI":"10.1016\/j.saa.2019.117213","article-title":"Spectroscopic and cytotoxicity studies on the combined interaction of (\u2212)-epigallocatechin-3-gallate and anthracycline drugs with human serum albumin","volume":"222","author":"Guo","year":"2019","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.saa.2015.11.010","article-title":"The increased binding affinity of curcumin with human serum albumin in the presence of rutin and baicalin: A potential for drug delivery system","volume":"155","author":"Liu","year":"2016","journal-title":"Spectrochim. Acta Part A Mol. Biomol. Spectrosc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1066","DOI":"10.1016\/j.ijbiomac.2017.09.080","article-title":"Decrease of the affinity of theophylline bind to serum proteins induced by flavonoids and their synergies on protein conformation","volume":"107","author":"Wang","year":"2018","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"141610","DOI":"10.1016\/j.foodchem.2024.141610","article-title":"Inhibition of coreopsin against \u03b1-amylase\/\u03b1-glucosidase and synergy with acarbose","volume":"464","author":"Cui","year":"2025","journal-title":"Food Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"136113","DOI":"10.1016\/j.foodchem.2023.136113","article-title":"Studies on the inhibition of \u03b1-glucosidase by biflavonoids and their interaction mechanisms","volume":"420","author":"Li","year":"2023","journal-title":"Food Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"106507","DOI":"10.1016\/j.bioorg.2023.106507","article-title":"Recent advances and future perspectives of noncompetitive proteasome inhibitors","volume":"135","author":"Zeng","year":"2023","journal-title":"Bioorg. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Baammi, S., El Allali, A., and Daoud, R. (2023). Unleashing Nature\u2019s potential: A computational approach to discovering novel VEGFR-2 inhibitors from African natural compound using virtual screening, ADMET analysis, molecular dynamics, and MMPBSA calculations. Front. Mol. Biosci., 10.","DOI":"10.3389\/fmolb.2023.1227643"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"129241","DOI":"10.1016\/j.ijbiomac.2024.129241","article-title":"Identification of isobenzofuranone derivatives as promising antidiabetic agents: Synthesis, in vitro and in vivo inhibition of \u03b1-glucosidase and \u03b1-amylase, computational docking analysis and molecular dynamics simulations","volume":"259","author":"Zahra","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"134878","DOI":"10.1016\/j.ijbiomac.2024.134878","article-title":"Alisol C 23-acetate might be a lead compound of potential lipase inhibitor from Alismatis rhizoma: Screening, identification and molecular dynamics simulation","volume":"278","author":"Gao","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"130535","DOI":"10.1016\/j.ijbiomac.2024.130535","article-title":"Deciphering the binding behavior and interaction mechanism of apigenin and \u03b1-glucosidase based on multi-spectroscopic and molecular simulation studies","volume":"264","author":"Liang","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1007\/s00894-023-05664-8","article-title":"Identification of potential RapJ hits as sporulation pathway inducer candidates in Bacillus coagulans via structure-based virtual screening and molecular dynamics simulation studies","volume":"29","author":"Mirmajidi","year":"2023","journal-title":"J. Mol. Model."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"11058","DOI":"10.1021\/ja910535j","article-title":"Constraining binding hot spots: NMR and molecular dynamics simulations provide a structural explanation for enthalpy\u2212entropy compensation in SH2\u2212ligand binding","volume":"132","author":"Ward","year":"2010","journal-title":"J. Am. Chem. Soc."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"108719","DOI":"10.1016\/j.rineng.2025.108719","article-title":"Molecular dynamics insights into allosteric and orthosteric co-targeting of Mycobacterium tuberculosis thymidylate kinase: A structure-based approach for bitopic ligand design","volume":"29","author":"Sivaprakasam","year":"2026","journal-title":"Results Eng."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e2310910120","DOI":"10.1073\/pnas.2310910120","article-title":"Intrinsic structural dynamics dictate enzymatic activity and inhibition","volume":"120","author":"Shukla","year":"2023","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"108495","DOI":"10.1016\/j.jmgm.2023.108495","article-title":"Intermediate-aided allostery mechanism for \u03b1-glucosidase by Xanthene-11v as an inhibitor using residue interaction network analysis","volume":"122","author":"Salehi","year":"2023","journal-title":"J. Mol. Graph. Model."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15634","DOI":"10.1080\/07391102.2023.2193643","article-title":"Binding order and apparent binding affinity in the bisubstrate activity of strictosidine synthase","volume":"41","author":"Kulhar","year":"2023","journal-title":"J. Biomol. Struct. Dyn."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e12898","DOI":"10.1111\/acel.12898","article-title":"Acarbose improves health and lifespan in aging HET3 mice","volume":"18","author":"Harrison","year":"2019","journal-title":"Aging Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.jff.2018.12.037","article-title":"Intestinal metabolism of baicalein after oral administration in mice: Pharmacokinetics and mechanisms","volume":"54","author":"Zhang","year":"2019","journal-title":"J. Funct. Foods"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"9822","DOI":"10.1021\/acs.jafc.1c04194","article-title":"Baicalein enhances the effect of acarbose on the improvement of nonalcoholic fatty liver disease associated with prediabetes via the inhibition of De Novo lipogenesis","volume":"69","author":"Xing","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"136102","DOI":"10.1016\/j.foodchem.2023.136102","article-title":"Inhibition mechanism of \u03b1-glucosidase inhibitors screened from Tartary buckwheat and synergistic effect with acarbose","volume":"420","author":"Han","year":"2023","journal-title":"Food Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"130979","DOI":"10.1016\/j.foodchem.2021.130979","article-title":"Exploring two types of prenylated bitter compounds from hop plant (Humulus lupulus L.) against \u03b1-glucosidase in vitro and in silico","volume":"370","author":"Wang","year":"2022","journal-title":"Food Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"108318","DOI":"10.1016\/j.foodhyd.2022.108318","article-title":"Exploring the binding mechanism of pumpkin seed protein and apigenin: Spectroscopic analysis, molecular docking and molecular dynamics simulation","volume":"137","author":"Liang","year":"2023","journal-title":"Food Hydrocoll."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"128616","DOI":"10.1016\/j.ijbiomac.2023.128616","article-title":"Hypoglycemic activity of immature persimmon (Diospyros kaki Thunb.) extracts and its inhibition mechanism for \u03b1-amylase and \u03b1-glucosidase","volume":"257","author":"Han","year":"2024","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"128149","DOI":"10.1016\/j.foodchem.2020.128149","article-title":"Bioactive flavonoids from Rubus corchorifolius inhibit \u03b1-glucosidase and \u03b1-amylase to improve postprandial hyperglycemia","volume":"341","author":"Tian","year":"2021","journal-title":"Food Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"145051","DOI":"10.1016\/j.ijbiomac.2025.145051","article-title":"Comprehending the mechanism of catechins against \u03b1-glucosidase by multispectral data and their antidiabetic effects in vivo","volume":"318","author":"Li","year":"2025","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"155836","DOI":"10.1016\/j.phymed.2024.155836","article-title":"Rhodiosin from Rhodiola crenulata effectively alleviate postprandial hyperglycemia by inhibiting both the activity and production of \u03b1-glucosidase","volume":"132","author":"Wang","year":"2024","journal-title":"Phytomedicine"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1215\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T01:47:10Z","timestamp":1785721630000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/19\/8\/1215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,1]]},"references-count":48,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ph19081215"],"URL":"https:\/\/doi.org\/10.3390\/ph19081215","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,1]]}}}