Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel

Significance Voltage-gated sodium (Na ᵥ) channels control neuronal signaling and are key targets for local anesthetics, antiepileptics, and therapeutics for a range of disorders. Multimicrosecond Anton simulations have provided completely unbiased molecular-level views of the interactions of lipophilic drugs with the recently solved bacterial channel, Na ᵥAb from Arcobacter butzleri . Newly parameterized benzocaine and phenytoin molecules exhibit different membrane partition coefficients, crossing rates and distributions around the channel, leading to the identification of distinct high- and low-affinity sites. We observe a minimum free energy pathway through membrane-bound fenestrations to a pore-blocking location, or from aqueous solution directly through the (closed) intracellular gate. These observations help explain experimental data and provide insight into Na ᵥ inhibition processes that will assist future drug development.