LAUSR

Voltage-gated Na+ (Nav) channels provide the basis for neuronal excitability in the brain. Of the nine Nav channel isoforms (Nav1.1-Nav1.9), Nav1.1 exhibits cell-specific distribution in fast-spiking parvalbumin (PV) interneurons in the cortical circuit. Reduced function of PV interneurons results in impairment of the cognitive domain, a bio-signature common to a variety of neuropsychiatric disorders. Thus, selective allosteric modulators targeting Nav1.1 might provide new means to rescue PV interneuron function and improve cognition. Previous studies have identified fibroblast growth factor 14 (FGF14) as a functionally relevant regulator of Nav1.1 channels. Binding of FGF14 to the Nav1.1 C-terminal tail results in modulation of Nav1.1-mediated peak transient currents and biophysical properties of the channel activation and steady-state inactivation. The FGF14:Nav1.1 protein:protein interaction (PPI) interface might therefore provide a novel target for the development of Nav1.1 allosteric modulators.In search of small molecules targeting Nav1.1, we conducted a ligand-based high-throughput virtual screening using a FGF14:Nav1.1 homology model based on available crystal structures of homologous proteins. The UCSF chimera software was used to determine the region of interaction between FGF14 and Nav1.1, and Autodock was used to create a grid box surrounding this area to identify critical amino acids at the PPI surface of FGF14.This region of interest was submitted to the Texas Advanced Computing Center (TACC) drug discovery database, which identified 1001 ZINC compounds out of 642,759 possible ligands against the interaction site. Scores ranged from −13 to 0, with lower scores indicating greater likelihood of binding to the FGF14 surface, and thus interfering with Nav 1.1 binding. On-going counter and orthogonal screenings using in heterologous systems as well as Schrodinger Advanced Drug Discovery Suite are being used to provide in-cell validation of 14 identified hits and understanding of the target-ligand interactions. These small molecules might represent a new class of PPI-based Nav1.1-specific allosteric modulators with applicability as cognitive enhancers.