Uncovering molecular determinants of potency and binding affinity in hit compounds targeting FGF14/Nav1.6 complex

Area of Science:

• Neuroscience
• Pharmacology
• Computational Chemistry

Background:

• Neuronal excitability is crucial for brain function and a target for neuropsychiatric disorder therapies.
• The protein-protein interaction (PPI) between fibroblast growth factor 14 (FGF14) and Nav1.6 channels is vital for neuronal excitability and a potential drug target.
• Understanding the physicochemical basis for small-molecule modulation of this FGF14-Nav1.6 interface is currently lacking.

Purpose of the Study:

• To elucidate structure-activity relationships for compounds targeting the FGF14-Nav1.6 PPI.
• To identify key physicochemical features governing compound potency and binding affinity.
• To guide the rational design of novel therapeutics for neuropsychiatric conditions.

Main Methods:

• Chemoinformatics analysis of 15 hit compounds from high-throughput screening.
• Utilized a descriptor-based approach to analyze structure-activity relationships.
• Correlated physicochemical features with compound potency and binding affinity data.

Main Results:

• Identified distinct sets of physicochemical features associated with compound potency.
• Identified separate features linked to binding affinity.
• Demonstrated that potency and binding affinity are influenced by largely independent molecular determinants.

Conclusions:

• Optimizing compound affinity does not necessarily impact potency, and vice versa.
• These findings provide a foundation for rational drug design targeting the FGF14-Nav1.6 PPI.
• Enables the development of first-in-class compounds to modulate neuronal excitability for therapeutic benefit.