{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:27:57Z","timestamp":1791325677168,"version":"4.3.1"},"reference-count":29,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T00:00:00Z","timestamp":1736467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Painless Research Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Kynurenine aminotransferase II (KAT-II) is a target for treating several diseases characterized by an excess of kynurenic acid (KYNA). Although KAT-II inactivators are available, they often lead to adverse side effects due to their irreversible inhibition mechanism. This study aimed to identify potent and safe inhibitors of KAT-II using computational and in vitro approaches. Methods: Virtual screening, MM\/GBSA, and molecular dynamics simulations were conducted to identify the top drug candidates, followed by kinetic measurements and in vitro cytotoxicity evaluation. Results: The study showed that two compounds, herbacetin and (-)-Epicatechin exhibited the best scores. Their Glide docking scores are \u22128.66 kcal\/mol and \u22128.16 kcal\/mol, respectively, and their MM\/GBSA binding energies are \u221250.30 kcal\/mol and \u221251.35 kcal\/mol, respectively. These scores are superior to those of the standard inhibitor, PF-04859989, which has docking scores of \u22127.12 kcal\/mol and binding energy of \u221238.41 kcal\/mol. ADMET analysis revealed that the selected compounds have favorable pharmacokinetic parameters, moderate bioavailability, and a safe toxicity profile, which supports their potential use. Further, the kinetic study showed that herbacetin and (-)-Epicatechin are reversible KAT-II inhibitors and exhibit a competitive inhibition mechanism. Their half-maximal inhibitory concentrations (IC50) are 5.98 \u00b1 0.18 \u00b5M and 8.76 \u00b1 0.76 \u00b5M, respectively. The MTT assay for cell toxicity indicated that the two compounds do not affect HepG2 cell viability at the necessary concentration for KAT-II inhibition. Conclusions: These results suggest that herbacetin and (-)-Epicatechin are suitable for KAT-II inhibition and are promising candidates for further development of KAT-II inhibitors.<\/jats:p>","DOI":"10.3390\/ph18010076","type":"journal-article","created":{"date-parts":[[2025,1,10]],"date-time":"2025-01-10T06:25:54Z","timestamp":1736490354000},"page":"76","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-7639","authenticated-orcid":false,"given":"Redouane","family":"Rebai","sequence":"first","affiliation":[{"name":"Department of Natural and Life Sciences, Faculty of Exact Sciences and Natural and Life Sciences, University Mohamed Khider of Biskra, BP145 RP, Biskra 07000, Algeria"},{"name":"Laboratory of Biotechnology, National Higher School of Biotechnology, Ville Universitaire (University of Constantine 3), Ali Mendjeli, BP E66, Constantine 25100, Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luc","family":"Jasmin","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Surgery, University of California, San Francisco, 707 Parnassus Ave Suite D-1201, San Francisco, CA 94143, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdennacer","family":"Boudah","sequence":"additional","affiliation":[{"name":"Laboratory of Biotechnology, National Higher School of Biotechnology, Ville Universitaire (University of Constantine 3), Ali Mendjeli, BP E66, Constantine 25100, Algeria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1021\/acsomega.8b02287","article-title":"Molecular dynamics simulation of kynurenine aminotransferase type II with nicotine as a ligand: A possible biochemical role of nicotine in schizophrenia","volume":"4","author":"Valencia","year":"2019","journal-title":"ACS Omega"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3679","DOI":"10.1038\/s41380-022-01552-4","article-title":"The tryptophan catabolite or kynurenine pathway in schizophrenia: Meta-analysis reveals dissociations between central, serum, and plasma compartments","volume":"27","author":"Almulla","year":"2022","journal-title":"Mol. 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