{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:48:31Z","timestamp":1792003711631,"version":"4.4.0"},"reference-count":29,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:00:00Z","timestamp":1790467200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["305182\/2021\u20108"],"award-info":[{"award-number":["305182\/2021\u20108"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["402311\/2024\u20108"],"award-info":[{"award-number":["402311\/2024\u20108"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["404652\/2025\u20105"],"award-info":[{"award-number":["404652\/2025\u20105"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,10,14]]},"abstract":"<jats:p>\n                    Cysteine proteases are recognized as relevant therapeutic targets in both parasitic diseases and cancer due to their essential biological functions. Among these enzymes, cruzain from\n                    <jats:italic>Trypanosoma cruzi<\/jats:italic>\n                    is an important molecular target for the treatment of Chagas disease. Likewise, human cathepsin L (hCatL) is a potential target for anticancer drug development. Both enzymes share conserved catalytic features, particularly the cysteine\u2013histidine catalytic dyad, which enables interaction with nitrile\u2010based reversible covalent inhibitors. Here, six nitrile\u2010derived inhibitors (\n                    <jats:bold>Neq1171.1, Neq1172.1, Neq1181.1, Neq1182.1, Neq1268, and Neq1276<\/jats:bold>\n                    ) had their cruzain and hCatL inhibition constants,\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>i<\/jats:sub>\n                    , determined. Besides, we have used molecular dynamics simulation and alchemical free energy calculations for evaluating the overall relative binding free energies of these inhibitors. The calculated free energy differences closely reproduced experimental trends, confirming the reliability of the computational protocol. These findings demonstrate that thermodynamic integration is an effective strategy for predicting relative binding affinities and provides valuable molecular\u2010level insights for the rational optimization of cysteine protease inhibitors with potential applications in Chagas disease and cancer therapy.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.70508","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T03:24:28Z","timestamp":1790565868000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Assessment of the Binding Affinity of Covalent Inhibitors of Cruzain and Cathepsin L Using Relative Binding Free Energy"],"prefix":"10.1002","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7419-1864","authenticated-orcid":false,"given":"Yan Carvalho","family":"Magno","sequence":"first","affiliation":[{"name":"Laborat\u00f3rio de Planejamento e Desenvolvimento de F\u00e1rmacos Instituto de Ci\u00eancias Exatas e Naturais Universidade Federal do Par\u00e1  Bel\u00e9m Par\u00e1 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3212-4513","authenticated-orcid":false,"given":"Luiz Fernando","family":"Barbosa","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo  S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2263-2124","authenticated-orcid":false,"given":"Maycon Vinicius Damasceno de","family":"Oliveira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Planejamento e Desenvolvimento de F\u00e1rmacos Instituto de Ci\u00eancias Exatas e Naturais Universidade Federal do Par\u00e1  Bel\u00e9m Par\u00e1 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7270-1517","authenticated-orcid":false,"given":"Jer\u00f4nimo","family":"Lameira","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Planejamento e Desenvolvimento de F\u00e1rmacos Instituto de Ci\u00eancias Exatas e Naturais Universidade Federal do Par\u00e1  Bel\u00e9m Par\u00e1 Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4963-0316","authenticated-orcid":false,"given":"Carlos A.","family":"Montanari","sequence":"additional","affiliation":[{"name":"Medicinal and Biological Chemistry Group S\u00e3o Carlos Institute of Chemistry University of S\u00e3o Paulo  S\u00e3o Carlos S\u00e3o Paulo Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,27]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1039\/C8CP03320J"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.9b00294"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio837"},{"key":"e_1_2_9_5_1","volume-title":"World Chagas Disease Day 2026: Women at the Heart: Protecting the Next Generation From Chagas Disease","author":"World Health Organization","year":"2026"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.2471\/B09621"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010021\u201002893\u20106"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2009.11.016"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1158\/1541\u20107786.MCR\u201007\u20100160"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2015.08.007"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.1c00515"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1039\/D2MD00204C"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1039\/C9CP04820K"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.9b01138"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.1740409"},{"key":"e_1_2_9_16_1","doi-asserted-by":"crossref","unstructured":"M. L. F.Barbosa D. F.Rossini M. E. R.Cardoso et al. \u201cThermodynamic Drivers of Covalent Cruzain Inhibition Beyond Enthalpy\u2010Entropy Compensation \u201d2025. ChemRxiv","DOI":"10.26434\/chemrxiv-2025-31hv6"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.202500630"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s42003\u2010023\u201005317\u20109"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003916"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct100578z"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.5b00255"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_2_9_23_1","volume-title":"Gaussian","author":"Frisch M. J.","year":"2016"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jcim.5c01063"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct1003687"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct200909j"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1021\/ct400314y"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540130805"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.21105\/joss.06934"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.2c00725"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70508","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cmdc.70508","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.70508","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T18:08:45Z","timestamp":1792001325000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.70508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,27]]},"references-count":29,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2026,10,14]]}},"alternative-id":["10.1002\/cmdc.70508"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.70508","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,27]]},"assertion":[{"value":"2026-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70508"}}