Identification of potent inhibitors of kynurenine-3-monooxygenase from natural products: In silico and in vitro approaches

• Published in: Heliyon 2024-05, Vol.10 (9), p.e30287-e30287, Article e30287
• Main Authors: Rebai, Redouane, Carmena-Bargueño, Miguel, Toumi, Mohammed Esseddik, Derardja, Imene, Jasmin, Luc, Pérez-Sánchez, Horacio, Boudah, Abdennacer
• Format: Article
• Language: English
• Subjects: apigenin; blood-brain barrier; computer simulation; drugs; Flavonoids; Kinetic assays; KMO inhibition; Molecular docking; Molecular dynamics; therapeutics
• ISSN: 2405-8440; 2405-8440
• DOI: 10.1016/j.heliyon.2024.e30287

Existing inhibitors of kynurenine-3-monooxygenase (KMO) have side effects and poorly cross the blood-brain barrier. Therefore, the discovery of new molecules targeting KMO isnecessary.This study aims to develop a novel therapeutic drug targeting KMO using computational methods and experimental validation of natural compounds.The results of our study show that the top four compounds, namely, 3′-Hydroxy-alpha-naphthoflavone exhibited the best docking scores with KMO (−10.0 kcal/mol), followed by 3′-Hydroxy-ss-naphthoflavone (−9.9 kcal/mol), genkwanin (−9.2 kcal/mol) and apigenin(-9.1 kcal/mol) respectively. Molecular dynamics was used to assess the stability of the primary target, KMO, and inhibitor complexes. We found stable interactions of 3′-Hydroxy-ss-naphthoflavone and apigenin with KMO up to 100 ns. Further, kinetic measurements showed that 3′-Hydroxy-alpha-naphthoflavone and 3′-Hydroxy-ss-naphthoflavone induce competitive inhibition with a good IC50 activity (15.85 ± 0.98 μM and 18.71 ± 0.78, respectively), while Genkwanin and Apigenin exhibit non-competitive inhibition mechanism (21.61 ± 0.97 μM and 24.14 ± 1.00 μM, respectively).Drug-likeness features and ADME analysis features also showed that the top four compounds could be used as potential candidates to replace the synthetic KMO inhibitor drugs with known side effects and poor brain-blood barrier penetration. [Display omitted] •The inhibitory effect of natural compounds with a similar structure to apigenin on KMO was investigated using molecular modeling.•The inhibitory effect of four lead compounds underwent a kinetic study to confirm the findings from docking and molecular dynamic simulations.•3′-Hydroxy-alpha-naphthoflavone, 3′-Hydroxy-ss-naphthoflavone, genkwanin and apigenin appeared to have the best potential to act as KMO inhibitors and display a suitable pharmacokinetic profile.