Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

• Published in: Molecules (Basel, Switzerland) Vol. 26; no. 11; p. 3314
• Main Authors: Gotina, Lizaveta, Seo, Seon Hee, Kim, Chae Won, Lim, Sang Min, Pae, Ae Nim
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 31.05.2021; MDPI
• Subjects: Alzheimer's disease; Amino acids; Binding; Blood-brain barrier; Cerebrospinal fluid; Competition; Computational neuroscience; Crystal structure; Drug development; flavoprotein hydroxylase; Fluorescence; Huntingtons disease; Hydrogen peroxide; Inhibitors; kynurenine monooxygenase; Ligands; Membrane permeability; Metabolites; Mimicry; Monooxygenase; Neurological disorders; Neurotoxicity; Optimization; Pathogenesis; Permeability; Pharmacology; pharmacophore; Pharmacophores; Pipeline design; Proteins; structure-based drug design; Therapeutic targets; Tryptophan; virtual screening
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules26113314

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline.