Targeting the CAPON-NOS Axis: A Computational Strategy for Small Molecule Modulator Discovery

Area of Science:

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

Background:

• Neuronal nitric oxide synthase (nNOS) interacts with the carboxy-terminal PDZ ligand of nNOS (CAPON) protein.
• This nNOS/CAPON interaction regulates nitric oxide (NO) signaling in neurological, cardiac, and metabolic functions.
• Dysregulation of nNOS/CAPON is implicated in various pathological conditions, presenting a therapeutic target.

Purpose of the Study:

• To develop the first strategy targeting the disruption of the nNOS/CAPON protein-protein interface.
• To identify small molecule modulators of the nNOS/CAPON interaction for potential therapeutic applications.
• To introduce novel computational tools to enhance structure-based drug discovery.

Main Methods:

• High-throughput virtual screening of 4.6 million compounds.
• Eight molecular dynamics simulations to analyze protein-protein interactions.
• Development of Python-based toolkits for NMR structural analysis and ligand preparation.

Main Results:

• Identification of two potential hit compounds capable of disrupting the nNOS/CAPON interface.
• Development of freely available computational tools that accelerate data preparation and reduce costs.
• Demonstration of a scalable computational framework for protein-protein interaction drug discovery.

Conclusions:

• This study presents a foundational strategy for developing targeted therapies for CAPON-mediated disorders.
• The identified compounds and novel computational tools represent significant advancements in drug discovery for nNOS/CAPON related conditions.
• The developed tools offer accessible resources for the research community to conduct efficient and reproducible virtual screening campaigns.