{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:12:10Z","timestamp":1784632330373,"version":"3.55.0"},"reference-count":23,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u221211.38 to \u221212.57 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\u2013ligand 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.<\/jats:p>","DOI":"10.3390\/ijms27146476","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:35:52Z","timestamp":1784630152000},"page":"6476","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Repurposing FDA-Approved Drugs as Nav1.7 Channel Modulators: An Integrated Structure-Based Virtual Screening and Molecular Dynamics Study"],"prefix":"10.3390","volume":"27","author":[{"given":"Mena","family":"Abdelsayed","sequence":"first","affiliation":[{"name":"Lankenau Institute for Medical Research, Philadelphia, PA 19096, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2939-7772","authenticated-orcid":false,"given":"Yassir","family":"Boulaamane","sequence":"additional","affiliation":[{"name":"Laboratory of Innovative Technologies, National School of Applied Sciences of Tangier, Abdelmalek Essaadi University, Tetouan 93000, Morocco"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1172\/JCI33297","article-title":"Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders","volume":"117","author":"Drenth","year":"2007","journal-title":"J. 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