{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:42:09Z","timestamp":1760060529417,"version":"build-2065373602"},"reference-count":81,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Computation"],"abstract":"<jats:p>Inhibitors of the tyrosine kinase Zap70 are actively searched to improve treatments of lymphoid malignancies and autoimmune diseases associated with an abnormal T-cell response. The natural product withaferin A (WFA) has been characterized as a covalent inhibitor of Zap70 capable of blocking the migration of human T-cells. By analogy, we postulated that other withanolides equipped with a thiol-reactive, \u03b1,\u03b2-unsaturated ketone may form covalent complexes with Zap70. The hypothesis was tested using a molecular modeling approach with a panel of 12 withanolides docked onto the kinase domain of Zap70. Seven natural products revealed a capability to form stable complexes with Zap70 comparable to that of WFA, including withangulatin A, 4\u03b2-hydroxywithanolide E, withaperuvin, and ixocarpalactone A. Withangulatin A surpassed all the other withanolides for its ability to engage an interaction with Zap70 kinase and to form covalent complexes via bonding to the Cys346 residue close to the enzyme active site. The physicochemical and ADMET properties of withangulatin A were analyzed via Density Functional Theory calculations and an analysis of its Fukui function descriptors. The C3 position of the enone moiety was identified as the most reactive (nucleophilic) site of the molecule. Withangulatin A revealed a satisfactory ADMET profile with no major toxicity anticipated. It represents a potential hit to guide the design of Zap70 inhibitors.<\/jats:p>","DOI":"10.3390\/computation13090207","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T13:27:44Z","timestamp":1756733264000},"page":"207","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Withangulatin A Identified as a Covalent Binder to Zap70 Kinase by Molecular Docking"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2430-3703","authenticated-orcid":false,"given":"Corentin","family":"Bedart","sequence":"first","affiliation":[{"name":"U1286\u2014INFINITE\u2014Institute for Translational Research in Inflammation, CHU Lille, Inserm, University of Lille, 59000 Lille, France"}]},{"given":"G\u00e9rard","family":"Vergoten","sequence":"additional","affiliation":[{"name":"U1286\u2014INFINITE\u2014Institute for Translational Research in Inflammation, CHU Lille, Inserm, University of Lille, 59000 Lille, France"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2973-9357","authenticated-orcid":false,"given":"Christian","family":"Bailly","sequence":"additional","affiliation":[{"name":"Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Facult\u00e9 de Pharmacie, University of Lille, 59000 Lille, France"},{"name":"UMR9020-U1277\u2014CANTHER\u2014Cancer Heterogeneity Plasticity and Resistance to Therapies, CHU Lille, Inserm, CNRS, University of Lille, 59000 Lille, France"},{"name":"OncoWitan, Scientific Consulting Office, 59290 Lille, France"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/imr.13058","article-title":"ZAP70, too little, too much can lead to autoimmunity","volume":"307","author":"Ashouri","year":"2022","journal-title":"Immunol. 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