In silico docking reveals possible Riluzole binding sites on Nav1.6 sodium channel: implications for drug design strategy on Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disorder involving primarily motor neurons (Hoffman 2008). Glutamate excitotoxicity has been suggested to contribute to this progressive loss of motor neurons due to astrocytes reduced ability to uptake this neurotransmitter (Van Den Bosch 2006). Previous reports revealed that the Na+ channel blockade may increase motor neurons survival against excitotoxic death by targeting the Sodium channel protein Nav1.6 (Hebert et al. 1994).
Riluzole interferes with glutamate-mediated transmission, thereby reducing excitotoxicity (Tavakoli 2002). These effects may be partly due to inactivation of voltage-dependent sodium channels Nav1.6 (Ajroud-Driss et al. 2007), suggesting an indirect effect of this drug on glutamate transporters. However many concerns are still unresolved due to experimental caveats, the lack of significant theoretical guidance (Fu et al. 2002) and experimental data on the structure of Riluzole-VGSc complexes.
In this study, we have integrated a docking analysis and homology modeling to understand the association of Riluzole with the alpha subunit of voltage-gated sodium channel Nav 1.6. First, we have constructed the three-dimensional structure model for the voltage-gated sodium channel subunit alpha Nav1.6 via homology modeling. Our results demonstrate that Riluzole interacts with the Nav1.6 channel, more specifically in the key residues TYR 1787, LEU 1843 and GLN 1799, suggesting possible cellular implications driven by these amino acids on Riluzole-Nav1.6 interaction, which may serve as an important output for a more specific and experimental drug design therapy against ALS

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