Repurposing FDA-Approved Drugs as Nav1.7 Channel Modulators: An Integrated Structure-Based Virtual Screening and Molecular Dynamics Study

The voltage-gated sodium channel Nav1.7 is a strongly validated target for the development of novel, non-opioid analgesics due to its genetic link to pain signaling. To accelerate the discovery of safe Nav1.7 modulators, this study outlines an integrated computational pipeline to repurpose FDA-approved drugs. A structurally complete model of the Nav1.7 central pore was generated via homology modeling from a high-resolution cryo-EM structure (PDB: 7W9K) to ensure a physically consistent model suitable for dynamic simulations. We conducted a structure-based virtual screening of 2296 FDA-approved compounds, identifying four promising candidates (DB04868, DB00941, DB01419, and DB15982) with strong predicted affinities ranging from −11.38 to −12.57 kcal/mol. Interaction fingerprinting revealed that binding is predominantly driven by hydrophobic contacts with conserved pore-lining residues, including Phe1503, Leu1010, and Ile1500. To validate these static predictions, the top protein–ligand complexes were subjected to single-replica 250 ns molecular dynamics (MD) simulations. Comprehensive trajectory analyses, including RMSD, RMSF, and principal component analysis, revealed a notable discrepancy between static docking scores and dynamic stability. The highest-scoring docking candidate, DB04868, exhibited substantial conformational flexibility and reduced stabilization under simulated physiological conditions. Conversely, DB01419, despite a lower initial docking rank, demonstrated the highest structural stability across all metrics and uniquely formed intermittent stabilizing hydrogen bonds. These findings underscore the value of post-docking MD validation in computational drug discovery and nominate DB01419 and DB15982 as candidate scaffolds that warrant subsequent experimental validation, including electrophysiological characterization and Nav-isoform selectivity profiling. We emphasize that these are computational predictions: in silico binding stability is not equivalent to functional inhibition of Nav1.7 currents, and the lead designations reported here remain hypothesis-generating until confirmed by patch-clamp and biochemical assays.

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