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

Identifying molecular mechanisms that regulate neuronal excitability is essential for developing targeted therapies for neuropsychiatric disorders. The protein–protein interaction (PPI) between fibroblast growth factor 14 (FGF14) and the voltage-gated Na⁺ channel Nav1.6 is critical in regulating neuronal excitability and has emerged as a promising drug target. However, the physicochemical features that drive small-molecule modulation of this interface remain elusive. Here, we apply a descriptor-based chemoinformatics approach to analyze 15 hit compounds identified via high-throughput screening, aiming to elucidate structure–activity relationships influencing their potency and binding affinity. The analysis revealed distinct subsets of physicochemical features strongly associated with either potency or binding affinity values, suggesting that these parameters are governed by largely independent molecular determinants. This independence implies that optimizing a compound for improved affinity need not compromise potency, and vice versa. Together, these findings may guide the rational optimization of first-in-class compounds aimed at controlling neuronal excitability through targeted PPI interface modulation.