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
Affiliations
Redouane Rebai
Department of Natural and Life Sciences, University Mohamed Khider of Biskra, BP 145 RP, 07000, Biskra, Algeria; Laboratory of biotechnology, National Higher School of Biotechnology, Ville universitaire (university of Constantine 3) Ali Mendjeli, BP E66 25100, Constantine, Algeria; Corresponding author. Department of Biology, Mohamed Khider University, PO Box 145 RP, Postal code: 07000 Biskra, Algeria.
Miguel Carmena-Bargueño
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
Mohammed Esseddik Toumi
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
Imene Derardja
Department of Natural and Life Sciences, University Mohamed Khider of Biskra, BP 145 RP, 07000, Biskra, Algeria
Luc Jasmin
Department of Oral and Maxillofacial Surgery, University of California, San Francisco, 707 Parnassus Ave Suite D-1201, San Francisco, CA, 94143, USA
Horacio Pérez-Sánchez
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
Abdennacer Boudah
Laboratory of biotechnology, National Higher School of Biotechnology, Ville universitaire (university of Constantine 3) Ali Mendjeli, BP E66 25100, Constantine, Algeria
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.
