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

Area of Science:

• Pharmacology
• Computational Chemistry
• Neuroscience

Background:

• The voltage-gated sodium channel Nav1.7 is a validated target for non-opioid analgesics.
• Genetic links to pain signaling highlight Nav1.7's therapeutic potential.

Purpose of the Study:

• To accelerate the discovery of safe Nav1.7 modulators by computationally repurposing FDA-approved drugs.
• To establish an integrated computational pipeline for identifying potential Nav1.7 inhibitors.

Main Methods:

• Generated a homology model of the Nav1.7 central pore using cryo-EM data (PDB: 7W9K).
• Performed structure-based virtual screening of 2296 FDA-approved compounds.
• Validated top candidates using 250 ns molecular dynamics (MD) simulations and trajectory analyses.

Main Results:

• Identified four promising candidates (DB04868, DB00941, DB01419, DB15982) with predicted affinities from -11.38 to -12.57 kcal/mol.
• Discovered that binding is primarily driven by hydrophobic interactions with conserved pore residues.
• MD simulations revealed DB01419 exhibited the highest structural stability, unlike the top-ranked DB04868.

Conclusions:

• Post-docking MD validation is crucial for assessing the dynamic stability of potential drug candidates.
• DB01419 and DB15982 are nominated as scaffolds for experimental validation as Nav1.7 modulators.
• Computational predictions require experimental confirmation via electrophysiology and biochemical assays.