Adaptive evolution and elucidating the potential inhibitor against schizophrenia to target DAOA (G72) isoforms

Area of Science:

• Neuroscience
• Pharmacology
• Computational Biology

Background:

• Schizophrenia (SZ) is a heritable mental disorder associated with neurophysiological and neuropsychological abnormalities.
• Overexpression of D-amino acid oxidase activator (DAOA) is implicated in neurotransmitter dysfunction, contributing to neurological disorders like SZ.

Purpose of the Study:

• To identify potential inhibitor compounds targeting DAOA isoforms.
• To investigate the binding interactions of a novel inhibitor with DAOA using computational methods.

Main Methods:

• A hybrid approach combining comparative modeling and molecular docking was employed.
• Two-dimensional similarity search was used to screen for potential inhibitors based on physiochemical properties.
• Molecular docking studies were performed to assess binding affinity and identify critical receptor-ligand interaction residues.

Main Results:

• A novel inhibitor compound demonstrated maximum binding affinity against four selected DAOA isoforms.
• Docking studies identified critical residues (e.g., Glu-53, Lys-120, Arg-122) involved in receptor-ligand interactions.
• Binding was observed in the conserved C-terminal region across the studied DAOA isoforms.

Conclusions:

• The identified inhibitor shows potential therapeutic value due to its high binding affinity and interaction with conserved regions of DAOA.
• Further studies, including site-directed mutagenesis, are recommended to explore ligand-binding pockets in detail.
• This research may aid in designing novel therapeutic strategies for schizophrenia.