Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study
<b>Background/Objectives:</b> 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 me...
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2025-01-01
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| author | Redouane Rebai Luc Jasmin Abdennacer Boudah |
| author_facet | Redouane Rebai Luc Jasmin Abdennacer Boudah |
| author_sort | Redouane Rebai |
| collection | DOAJ |
| description | <b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> The study showed that two compounds, herbacetin and (-)-Epicatechin exhibited the best scores. Their Glide docking scores are −8.66 kcal/mol and −8.16 kcal/mol, respectively, and their MM/GBSA binding energies are −50.30 kcal/mol and −51.35 kcal/mol, respectively. These scores are superior to those of the standard inhibitor, PF-04859989, which has docking scores of −7.12 kcal/mol and binding energy of −38.41 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 ± 0.18 µM and 8.76 ± 0.76 µM, 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. <b>Conclusions:</b> These results suggest that herbacetin and (-)-Epicatechin are suitable for KAT-II inhibition and are promising candidates for further development of KAT-II inhibitors. |
| format | Article |
| id | doaj-art-13347157b19942c8895a9b35e1d58879 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj-art-13347157b19942c8895a9b35e1d588792025-01-24T13:45:18ZengMDPI AGPharmaceuticals1424-82472025-01-011817610.3390/ph18010076Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro StudyRedouane Rebai0Luc Jasmin1Abdennacer Boudah2Department of Natural and Life Sciences, Faculty of Exact Sciences and Natural and Life Sciences, University Mohamed Khider of Biskra, BP145 RP, Biskra 07000, AlgeriaDepartment of Oral and Maxillofacial Surgery, University of California, San Francisco, 707 Parnassus Ave Suite D-1201, San Francisco, CA 94143, USALaboratory of Biotechnology, National Higher School of Biotechnology, Ville Universitaire (University of Constantine 3), Ali Mendjeli, BP E66, Constantine 25100, Algeria<b>Background/Objectives:</b> 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. <b>Methods:</b> 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. <b>Results:</b> The study showed that two compounds, herbacetin and (-)-Epicatechin exhibited the best scores. Their Glide docking scores are −8.66 kcal/mol and −8.16 kcal/mol, respectively, and their MM/GBSA binding energies are −50.30 kcal/mol and −51.35 kcal/mol, respectively. These scores are superior to those of the standard inhibitor, PF-04859989, which has docking scores of −7.12 kcal/mol and binding energy of −38.41 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 ± 0.18 µM and 8.76 ± 0.76 µM, 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. <b>Conclusions:</b> These results suggest that herbacetin and (-)-Epicatechin are suitable for KAT-II inhibition and are promising candidates for further development of KAT-II inhibitors.https://www.mdpi.com/1424-8247/18/1/76herbacetin(-)-EpicatechinKAT-II inhibitionmolecular dockingmolecular dynamics |
| spellingShingle | Redouane Rebai Luc Jasmin Abdennacer Boudah Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study Pharmaceuticals herbacetin (-)-Epicatechin KAT-II inhibition molecular docking molecular dynamics |
| title | Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study |
| title_full | Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study |
| title_fullStr | Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study |
| title_full_unstemmed | Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study |
| title_short | Identification of Two Flavonoids as New and Safe Inhibitors of Kynurenine Aminotransferase II via Computational and In Vitro Study |
| title_sort | identification of two flavonoids as new and safe inhibitors of kynurenine aminotransferase ii via computational and in vitro study |
| topic | herbacetin (-)-Epicatechin KAT-II inhibition molecular docking molecular dynamics |
| url | https://www.mdpi.com/1424-8247/18/1/76 |
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