{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:09:19Z","timestamp":1791083359773,"version":"4.1.0"},"reference-count":47,"publisher":"Wiley","issue":"16","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,8,27]]},"abstract":"<jats:p>\n                    Although chlorogenic acid, suramin, ursolic acid, and the glycyrrhetinic acid derivative FC122 are individually known PTP1B inhibitors, no study has systematically characterized how mechanistic diversity determines the pharmacological outcome of their combinations. Here, we integrate experimental enzyme kinetics, molecular docking, molecular dynamics (MD), and membrane permeability simulations to address this question. Individual inhibitory potencies ranked SUR\u2009&gt;\u2009FC122\u2009&gt;\u2009UA\u2009&gt;\u2009CGA (IC\n                    <jats:sub>50<\/jats:sub>\n                    : 1.82, 3.27, 6.12, and 252\u2009\u00b5M, respectively). Fixed\u2010ratio combination experiments showed two distinct profiles: additivity for the uncompetitive\u2009+\u2009mixed pair (FC122\u2009+\u2009UA) and competitive\u2009+\u2009competitive pairs (SUR\u2009+\u2009CGA), and antagonism for the competitive\u2009+\u2009uncompetitive combination (SUR\u2009+\u2009FC122). Docking and MD provided the structural basis for these results and suggested that each combination imposes a distinct structural flexibility profile on the disordered C\u2010terminal region of PTP1B (residues 300\u2013400). For the first time, the MD\u2010AMBER\u2010Umbrella\u2010COM protocol was applied to generate a comparative membrane permeability profile for mechanistically diverse PTP1B inhibitors, proposing a permeability order (SUR\u2009&gt;\u2009FC122\u2009&gt;\u2009CGA\u2009\u2248\u2009UA). These results suggest that kinetic compatibility is a more reliable predictor of promising inhibitor combinations than binding\u2010site geography alone, and they offer a rational framework for designing multisite PTP1B inhibition strategies in type 2 diabetes mellitus.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70446","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T04:23:33Z","timestamp":1787199813000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Kinetic Compatibility as a Predictor of PTP1B Inhibitor Combination Outcomes: An Integrated Experimental and Computational Study"],"prefix":"10.1002","volume":"21","author":[{"given":"Jonathan","family":"Trapala","sequence":"first","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4321-3642","authenticated-orcid":false,"given":"Laura I.","family":"\u00c1lvarez\u2010A\u00f1orve","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2154-1802","authenticated-orcid":false,"given":"Nathaly","family":"Vasquez\u2010Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1012-2760","authenticated-orcid":false,"given":"Erika","family":"Chavira\u2010Su\u00e1rez","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8052-7800","authenticated-orcid":false,"given":"Luz","family":"V\u00e1squez\u2010Bochm","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deyamira","family":"Matuz\u2010Mares","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3954-8220","authenticated-orcid":false,"given":"Francisco","family":"Cort\u00e9s\u2010Ben\u00edtez","sequence":"additional","affiliation":[{"name":"Laboratorio de S\u00edntesis y Aislamiento de Sustancias Bioactivas Departamento de Sistemas Biol\u00f3gicos Divisi\u00f3n de Ciencias Biol\u00f3gicas y de la Salud Universidad Aut\u00f3noma Metropolitana \u2010 Unidad Xochimilco  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8910-3035","authenticated-orcid":false,"given":"Martin","family":"Gonz\u00e1lez\u2010Andrade","sequence":"additional","affiliation":[{"name":"Departamento de Bioqu\u00edmica Facultad de Medicina Universidad Nacional Aut\u00f3noma de M\u00e9xico  Ciudad de M\u00e9xico M\u00e9xico"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc22-S016"},{"issue":"13","key":"e_1_2_8_3_1","first-page":"4892","article-title":"Design, synthesis, molecular docking and anticancer activity evaluation of methyl salicylate based thiazoles as PTP1B inhibitors","volume":"25","author":"Ko\u0142odziej\u2010Sobczak D.","year":"2024","journal-title":"International Journal of Molecular Sciences"},{"key":"e_1_2_8_4_1","volume-title":"IDF Diabetes Atlas","author":"Federation I. 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