Targeting CAPON to modulate the CAPON-NOS Axis: a computational approach

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• The carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) is a crucial regulator of nitric oxide (NO) signaling.
• Dysregulation of CAPON impacts neurological, cardiac, and metabolic functions, making it a significant therapeutic target.
• A lack of specific modulators for CAPON or the nNOS/CAPON complex presents a gap in drug discovery.

Purpose of the Study:

• To develop the first strategy targeting the disruption of the nNOS/CAPON protein-protein interface.
• To identify potential therapeutic agents for CAPON-mediated disorders.
• To introduce novel computational tools for accelerating drug discovery.

Main Methods:

• Screening of a large chemical library (4.6 million compounds).
• Utilizing 13 molecular dynamics simulations.
• Developing and applying three Python-based drug discovery tools for NMR analysis, ligand preparation, and hit prioritization.

Main Results:

• Identification of nine potential hit compounds that disrupt the nNOS/CAPON interface.
• Development of a scalable computational framework for drug discovery.
• Creation of automated tools for virtual screening and hit prioritization.

Conclusions:

• This study provides a foundational strategy for developing targeted therapies against CAPON-mediated disorders.
• The identified hit compounds represent promising starting points for further drug development.
• The novel Python-based tools accelerate the drug discovery pipeline for protein-protein interaction targets.