{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:45:50Z","timestamp":1791812750442,"version":"4.3.4"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005825","name":"National Institute of Food and Agriculture","doi-asserted-by":"publisher","award":["VA-160211"],"award-info":[{"award-number":["VA-160211"]}],"id":[{"id":"10.13039\/100005825","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM133754"],"award-info":[{"award-number":["R35GM133754"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000078","name":"Division of Materials Research","doi-asserted-by":"publisher","award":["1933525"],"award-info":[{"award-number":["1933525"]}],"id":[{"id":"10.13039\/100000078","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Carbohydrate-digesting enzymes, including pancreatic \u03b1-amylase and maltase-glucoamylase (MGAM), are important therapeutic targets for type 2 diabetes due to their role in regulating glucose production. In this study, molecular dynamics (MD) simulations were performed to investigate the stability and interaction patterns of inhibitors identified through SILCS-based virtual screening. Representative ligands for the N-terminal and C-terminal domains of MGAM (NtMGAM, CtMGAM), and \u03b1-amylase were parametrized using both the nonpolarizable CHARMM and polarizable Drude force fields based on quantum mechanical (QM) reference data. MD simulations of the apo enzymes show that their overall structures remain stable, with flexibility primarily localized to regions surrounding the catalytic pockets. Simulations of the enzyme\u2013ligand complexes demonstrate that the ligands remain associated with the binding regions throughout the trajectories. Comparison between the two force fields reveals distinct interaction patterns: CHARMM interactions are largely driven by a small number of dominant contacts, whereas the Drude model captures a more extensive and cooperative interaction network. Notably, the Drude model enables enhanced engagement with catalytic residues in NtMGAM, whereas ligand binding in CtMGAM and \u03b1-amylase remains more flexible and less directly coupled to the catalytic machinery. These results highlight the importance of polarization in describing enzyme\u2013ligand interactions and suggest that polarization can influence the balance and persistence of interactions in a system-dependent manner. These findings provide further computational support for the candidate inhibitors identified through computational screening.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c01734","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:02:10Z","timestamp":1790769730000},"page":"12955-12968","source":"Crossref","is-referenced-by-count":0,"title":["Computer-Aided Drug Design for Type 2 Diabetes-Related\nEnzymes: Polarizable and Nonpolarizable Simulations of Enzyme-Inhibitor\nComplexes"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2631-4990","authenticated-orcid":true,"given":"Esmat","family":"Mohammadi","sequence":"first","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6661-8653","authenticated-orcid":true,"given":"Justin A.","family":"Lemkul","sequence":"additional","affiliation":[{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]},{"name":"Virginia Tech , , , ,","place":["Blacksburg, Virginia, United States, 24061"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"issue":"23","key":"2026101208070407500_cit1","doi-asserted-by":"publisher","first-page":"17763","DOI":"10.1074\/jbc.M109.078980","article-title":"Structural\nbasis for substrate selectivity in human\nmaltase-glucoamylase and sucrase-isomaltase N-terminal domains","volume":"285","author":"Sim","year":"2010","journal-title":"J. Biol. Chem."},{"issue":"7","key":"2026101208070407500_cit2","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1002\/star.201000150","article-title":"Human \u03b1-amylase\nand starch\ndigestion: An interesting marriage","volume":"63","author":"Butterworth","year":"2011","journal-title":"Starch-Sta\u0308rke"},{"issue":"8","key":"2026101208070407500_cit3","doi-asserted-by":"publisher","first-page":"2343","DOI":"10.1021\/acs.jpcb.5c07277","article-title":"Insights into the Electronic and Structural Properties\nof Cellulose and Amylose: A Comparative Force Field Study","volume":"130","author":"Mohammadi","year":"2026","journal-title":"J. Phys. Chem. 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Nutr."},{"issue":"2","key":"2026101208070407500_cit5","doi-asserted-by":"publisher","first-page":"201","DOI":"10.3390\/ph18020201","article-title":"Buzhong\nyiqi formula alleviates postprandial hyperglycemia in T2DM rats by\ninhibiting \u03b1-amylase and \u03b1-glucosidase in vitro and in\nvivo","volume":"18","author":"Zeng","year":"2025","journal-title":"Pharmaceuticals"},{"issue":"9","key":"2026101208070407500_cit6","doi-asserted-by":"publisher","first-page":"1730","DOI":"10.1002\/pro.5560040908","article-title":"The structure\nof human pancreatic \u03b1-amylase at\n1.8 \u00c5 resolution and comparisons with related enzymes","volume":"4","author":"Brayer","year":"1995","journal-title":"Protein Sci."},{"issue":"1","key":"2026101208070407500_cit7","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S0167-4838(00)00302-2","article-title":"Relationship of sequence\nand structure to specificity in the \u03b1-amylase family of enzymes","volume":"1546","author":"MacGregor","year":"2001","journal-title":"Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol."},{"issue":"6","key":"2026101208070407500_cit8","doi-asserted-by":"publisher","first-page":"1189","DOI":"10.2147\/VHRM.S3119","article-title":"Alpha-glucosidase inhibitors in the early treatment\nof type 2 diabetes","volume":"4","author":"Van de Laar","year":"2008","journal-title":"Vasc. Health Risk Manage."},{"issue":"3","key":"2026101208070407500_cit9","doi-asserted-by":"publisher","first-page":"782","DOI":"10.1016\/j.jmb.2007.10.069","article-title":"Human intestinal\nmaltase\u2013glucoamylase: crystal structure of the N-terminal catalytic\nsubunit and basis of inhibition and substrate specificity","volume":"375","author":"Sim","year":"2008","journal-title":"J. Mol. Biol."},{"issue":"7","key":"2026101208070407500_cit10","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/nrd1129","article-title":"Implications\nof protein flexibility for drug discovery","volume":"2","author":"Teague","year":"2003","journal-title":"Nat.\nRev. 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SILCS-Based Fragment\nMapping, Pharmacophore Modeling, and Virtual Screening","author":"Mohammadi","DOI":"10.1021\/acs.jcim.6c01733"},{"issue":"4","key":"2026101208070407500_cit14","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1002\/jcc.21367","article-title":"CHARMM\ngeneral force field: A force field for\ndrug-like molecules compatible with the CHARMM all-atom additive biological\nforce fields","volume":"31","author":"Vanommeslaeghe","year":"2010","journal-title":"J. Comput. Chem."},{"issue":"12","key":"2026101208070407500_cit15","doi-asserted-by":"publisher","first-page":"3144","DOI":"10.1021\/ci300363c","article-title":"Automation of the CHARMM General\nForce Field (CGenFF) I: bond perception and atom typing","volume":"52","author":"Vanommeslaeghe","year":"2012","journal-title":"J. Chem. Inf. Model."},{"key":"2026101208070407500_cit16","unstructured":"Frisch, M. J.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. 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