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

Redouane Rebai; Miguel Carmena-Bargueño; Mohammed Esseddik Toumi; Imene Derardja; Luc Jasmin; Horacio Pérez-Sánchez; Abdennacer Boudah

doi:10.1016/j.heliyon.2024.e30287

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

Heliyon. 2024 Apr 26;10(9):e30287. doi: 10.1016/j.heliyon.2024.e30287. eCollection 2024 May 15.

Authors

Redouane Rebai^{1

2}, Miguel Carmena-Bargueño³, Mohammed Esseddik Toumi⁴, Imene Derardja¹, Luc Jasmin⁵, Horacio Pérez-Sánchez³, Abdennacer Boudah²

Affiliations

¹ Department of Natural and Life Sciences, University Mohamed Khider of Biskra, BP 145 RP, 07000, Biskra, Algeria.
² Laboratory of biotechnology, National Higher School of Biotechnology, Ville universitaire (university of Constantine 3) Ali Mendjeli, BP E66 25100, Constantine, Algeria.
³ Structural Bioinformatics and High-Performance Computing Research Group (BIO-HPC), Computer Engineering Department, Universidad Católica de Murcia (UCAM), Campus de los Jerónimos 135, 30107, Guadalupe, Spain.
⁴ Laboratory of Microbiological Engineering and Application, Biochemistry and Molecular and Cellular Biology Department, Faculty of Nature and Life Sciences, University of Mentouri Brothers Constantine 1, Constantine, 25017, Algeria.
⁵ Department of Oral and Maxillofacial Surgery, University of California, San Francisco, 707 Parnassus Ave Suite D-1201, San Francisco, CA, 94143, USA.

Abstract

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.

Keywords: Flavonoids; KMO inhibition; Kinetic assays; Molecular docking; Molecular dynamics.