{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:05Z","timestamp":1788221585681,"version":"build-2803163510"},"reference-count":39,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/na","name":"Department of Science and Technology, Philippines","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Inhibition of human dipeptidyl peptidase IV (hDPP-IV) is considered an effective strategy in the management of type 2 diabetes (T2D). However, the lack of high-throughput screening approaches and the high cost of experimental evaluation have limited the discovery of peptide-based hDPP-IV inhibitors. Herein, an integrated multicomputational screening strategy was employed to successfully mine novel hDPP-IV inhibitory tripeptides. Among the screened candidates, FAW exhibited the highest inhibitory activity, with an IC50 of 233 \u03bcM, establishing it as a promising scaffold for further development. Structural-based density functional theory (DFT) analysis revealed that active tripeptides exhibit localized electronic regions with higher electrophilicity indices than less active tripeptides. Furthermore, experimental evaluation demonstrated that stereospecific recognition of l-alanine by hDPP-IV plays a critical role in FAW\u2019s inhibitory activity. Molecular dynamics simulation further indicated that the FAW-hDPP-IV complex induces less conformational perturbation in the enzyme than the d-alanine-containing analogue. Collectively, the agreement between the multicomputational screening and the in vitro validation results offers a valuable strategy for mining other short-chain bioactive peptide candidates that may inhibit hDPP-IV.<\/jats:p>","DOI":"10.1021\/acsomega.6c01462","type":"journal-article","created":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T01:01:14Z","timestamp":1786755674000},"page":"49139-49150","source":"Crossref","is-referenced-by-count":0,"title":["Mining of Novel\nHuman DPP-IV-Targeting Tripeptides\nthrough Multicomputational Screening and In Vitro Validation for Diabetes\nTherapy"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-0175-3866","authenticated-orcid":true,"suffix":"Jr.","given":"James V.","family":"Lavilla","sequence":"first","affiliation":[{"name":"Mindanao State University \u2212 Iligan Institute of Technology , , , ,","place":["Iligan City, Lanao del Norte, Philippines, 9200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis Kirby B.","family":"Burnea","sequence":"additional","affiliation":[{"name":"Mindanao State University \u2212 Iligan Institute of Technology , , , ,","place":["Iligan City, Lanao del Norte, Philippines, 9200"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0916-1233","authenticated-orcid":true,"given":"Hironobu","family":"Hojo","sequence":"additional","affiliation":[{"name":"The University of Osaka , , 3-2 Yamadaoka , , ,","place":["Suita, Osaka, Japan, 565\u22120871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2531-6821","authenticated-orcid":true,"given":"Changge","family":"Guan","sequence":"additional","affiliation":[{"name":"University of Pennsylvania , , , ,","place":["Philadelphia, Pennsylvania, United States, 19104-6243"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"Charlie A.","family":"Lavilla","sequence":"additional","affiliation":[{"name":"Mindanao State University \u2212 Iligan Institute of Technology , , , ,","place":["Iligan City, Lanao del Norte, Philippines, 9200"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026083119142636500_cit1","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.tifs.2022.10.007","article-title":"The improvement of sulforaphane in type 2 diabetes mellitus (T2DM)\nand related complications: A review","volume":"129","author":"Wang","year":"2022","journal-title":"Trends\nFood Sci. Technol."},{"key":"2026083119142636500_cit2","doi-asserted-by":"publisher","first-page":"1987","DOI":"10.3390\/molecules25081987","article-title":"Type 2 diabetes\nmellitus: a review of multi-target drugs","volume":"25","author":"Artasensi","year":"2020","journal-title":"Molecules"},{"issue":"1","key":"2026083119142636500_cit3","doi-asserted-by":"publisher","first-page":"7749","DOI":"10.1038\/s41598-024-58485-x","article-title":"A combination of virtual\nscreening, molecular dynamics simulation, MM\/PBSA, ADMET, and DFT\ncalculations to identify a potential DPP4 inhibitor","volume":"14","author":"Zare","year":"2024","journal-title":"Sci. Rep."},{"issue":"1","key":"2026083119142636500_cit4","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1007\/s11033-025-10235-6","article-title":"DPP4, a potential\ntumor biomarker, and tumor therapeutic\ntarget","volume":"52","author":"Sun","year":"2025","journal-title":"Mol. Biol. 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Chem."},{"key":"2026083119142636500_cit9","doi-asserted-by":"publisher","first-page":"291","DOI":"10.1016\/j.diabres.2007.08.021","article-title":"Efficacy and safety of sitagliptin monotherapy in Japanese\npatients\nwith type 2 diabetes","volume":"79","author":"Nonaka","year":"2008","journal-title":"Diabetes Res. Clin. Pract."},{"key":"2026083119142636500_cit10","doi-asserted-by":"publisher","first-page":"10604","DOI":"10.1021\/acs.jafc.9b03164","article-title":"In vitro metabolic stability\nof a casein-derived dipeptidyl peptidase-IV\n(DPP-IV) inhibitory peptide VPYPQ and its controlled release from\ncasein by enzymatic hydrolysis","volume":"67","author":"Zheng","year":"2019","journal-title":"J. Agric. Food\nChem."},{"key":"2026083119142636500_cit11","doi-asserted-by":"publisher","first-page":"12749","DOI":"10.1021\/acs.jafc.3c04940","article-title":"Transepithelial transport of the bifunctional peptide IPYWTY indirectly\ninduced insulin release mediated by active GLP-1","volume":"71","author":"Zhang","year":"2023","journal-title":"J. Agric. Food Chem."},{"key":"2026083119142636500_cit12","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1080\/10408398.2022.2120454","article-title":"Food-derived dipeptidyl peptidase IV inhibitory peptides:\nProduction,\nidentification, structure-activity relationship, and their potential\nrole in glycemic regulation","volume":"64","author":"Zhang","year":"2024","journal-title":"Crit. Rev. Food\nSci. 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Biotechnol."},{"key":"2026083119142636500_cit15","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e35191","article-title":"Identification of potential dipeptidyl peptidase IV\ninhibitors from the ConMedNP library by virtual screening, and molecular\ndynamics methods","volume":"10","author":"Fofack","year":"2024","journal-title":"Heliyon"},{"key":"2026083119142636500_cit16","doi-asserted-by":"publisher","first-page":"144979","DOI":"10.1016\/j.foodchem.2025.144979","article-title":"DPP-IV inhibitory\npeptides from highland barley via machine learning and multi-scale\nvalidation","volume":"489","author":"Bao","year":"2025","journal-title":"Food Chem."},{"key":"2026083119142636500_cit17","doi-asserted-by":"publisher","first-page":"129191","DOI":"10.1016\/j.ijbiomac.2023.129191","article-title":"Identification, characterization, and insights into the mechanism\nof novel dipeptidyl peptidase-IV inhibitory peptides from yak hemoglobin\nby in silico exploration, molecular docking, and in vitro assessment","volume":"259","author":"Zhang","year":"2024","journal-title":"Int. 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Macromol."},{"key":"2026083119142636500_cit18","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1007\/978-1-4939-3569-7_3","article-title":"Binding site prediction of proteins with organic\ncompounds or peptides using GALAXY web servers","volume-title":"Computational Design of Ligand Binding Proteins","author":"Heo","year":"2016"},{"key":"2026083119142636500_cit19","doi-asserted-by":"publisher","first-page":"39662","DOI":"10.1021\/acsomega.3c05571","article-title":"Exploration of DPP-IV\ninhibitory peptide design rules assisted by\nthe deep learning pipeline that identifies the restriction enzyme\ncutting site","volume":"8","author":"Guan","year":"2023","journal-title":"ACS Omega"},{"key":"2026083119142636500_cit20","doi-asserted-by":"publisher","first-page":"W443","DOI":"10.1093\/nar\/gky357","article-title":"HPEPDOCK: a web server for blind\npeptide\u2013protein docking based on a hierarchical algorithm","volume":"46","author":"Zhou","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2026083119142636500_cit21","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.foodchem.2014.11.131","article-title":"Analyzing a dipeptide library to identify human dipeptidyl\npeptidase IV inhibitor","volume":"175","author":"Lan","year":"2015","journal-title":"Food Chem."},{"key":"2026083119142636500_cit22","unstructured":"Schro\u0308dinger, L.; DeLano, W. P.\n          PyMOL\n2020; 2023. http:\/\/www.pymol.org\/pymol."},{"key":"2026083119142636500_cit23","doi-asserted-by":"publisher","first-page":"426","DOI":"10.6026\/97320630008426","article-title":"Identifications small molecules inhibitor\nof p53-mortalin complex for cancer drug using virtual screening","volume":"8","author":"Utomo","year":"2012","journal-title":"Bioinformation"},{"key":"2026083119142636500_cit24","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1016\/j.bbrc.2013.03.010","article-title":"A comparative study of the binding modes of recently launched dipeptidyl\npeptidase IV inhibitors in the active site","volume":"434","author":"Nabeno","year":"2013","journal-title":"Biochem. Biophys. Res. 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Int."},{"key":"2026083119142636500_cit28","doi-asserted-by":"publisher","first-page":"2886","DOI":"10.1080\/07391102.2023.2214230","article-title":"Role of deleterious nsSNPs of klotho\nprotein and their\ndrug response: A computational mechanical insights","volume":"42","author":"Jayaraj","year":"2024","journal-title":"J. Biomol. Struct. Dyn."},{"key":"2026083119142636500_cit29","doi-asserted-by":"publisher","first-page":"102217","DOI":"10.1016\/j.fochx.2025.102217","article-title":"Screening and evaluation of novel DPP-IV inhibitory\npeptides in goat\nmilk based on molecular docking and molecular dynamics simulation","volume":"25","author":"Dang","year":"2025","journal-title":"Food Chem."},{"key":"2026083119142636500_cit30","doi-asserted-by":"publisher","first-page":"106449","DOI":"10.1016\/j.compbiomed.2022.106449","article-title":"SARS-CoV-2\nproteases Mpro and PLpro: Design of inhibitors with predicted high\npotency and low mammalian toxicity using artificial neural networks,\nligand-protein docking, molecular dynamics simulations, and ADMET\ncalculations","volume":"153","author":"Tumskiy","year":"2023","journal-title":"Comput. Biol. Med."},{"key":"2026083119142636500_cit31","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1038\/s41573-022-00542-z","article-title":"Advances\nin covalent drug discovery","volume":"21","author":"Boike","year":"2022","journal-title":"Nat. Rev. Drug Discovery"},{"key":"2026083119142636500_cit32","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1088\/0034-4885\/64\/4\/203","article-title":"Protein structure:\ngeometry, topology andclassification","volume":"64","author":"Taylor","year":"2001","journal-title":"Rep. Prog.\nPhys."},{"key":"2026083119142636500_cit33","doi-asserted-by":"publisher","first-page":"735","DOI":"10.1007\/s10989-020-10122-7","article-title":"Strategic preparations\nof DPP-IV inhibitory peptides from Val-Pro-Xaa and Ile-Pro-Xaa peptide\nmixtures","volume":"27","author":"Guan","year":"2021","journal-title":"Int. J. Pept. Res. Ther."},{"key":"2026083119142636500_cit34","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2020.e04227","article-title":"Hydrophobic\ninteractions at subsite\nS1\u2032 of human dipeptidyl peptidase IV contribute significantly\nto the inhibitory effect of tripeptides","volume":"6","author":"Araki","year":"2020","journal-title":"Heliyon"},{"key":"2026083119142636500_cit35","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1016\/S0014-5793(99)01166-7","article-title":"Two highly conserved glutamic acid\nresidues in the predicted \u03b2 propeller domain of dipeptidyl peptidase\nIV are required for its enzyme activity","volume":"458","author":"Abbott","year":"1999","journal-title":"FEBS\nLett."},{"key":"2026083119142636500_cit36","doi-asserted-by":"publisher","first-page":"W294","DOI":"10.1093\/nar\/gks493","article-title":"GalaxyWEB server for\nprotein structure prediction and refinement","volume":"40","author":"Ko","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"2026083119142636500_cit37","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1007\/978-1-0716-4562-8_25","article-title":"Ultra-Efficient\nSolid-Phase Peptide Synthesis","volume-title":"Peptide\nSynthesis","author":"Singh","year":"2025"},{"key":"2026083119142636500_cit38","doi-asserted-by":"publisher","first-page":"2744","DOI":"10.1021\/ct900347f","article-title":"Comparison of global reactivity descriptors\ncalculated using various density functionals: a QSAR perspective","volume":"5","author":"Vijayaraj","year":"2009","journal-title":"J. Chem. Theory Comput."},{"key":"2026083119142636500_cit39","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1038\/nmeth.4067","article-title":"CHARMM36m: an improved force field for folded and intrinsically disordered\nproteins","volume":"14","author":"Huang","year":"2017","journal-title":"Nat. Methods"}],"container-title":["ACS Omega"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acsomega.6c01462","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49139\/66580247\/acsomega.6c01462.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/acsodf\/article-pdf\/11\/33\/49139\/66580247\/acsomega.6c01462.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:14:37Z","timestamp":1788218077000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/acsodf\/article\/11\/33\/49139\/5257676\/Mining-of-Novel-Human-DPP-IV-Targeting-Tripeptides"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":39,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,14]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acsomega.6c01462","relation":{},"ISSN":["2470-1343"],"issn-type":[{"value":"2470-1343","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}