Studies on human genetics have implicated the voltage-gated sodium channel Nav1.7 as an appealing target for the treatment of pain. In this study, we put forward a ligand-based pharmacophore for the first time, which was generated by a set of multiple chemical scaffolds including sulfonamide and non-sulfonamide derivatives and consisted of four chemical features: an aromatic ring, a hydrophobic group and two hydrogen acceptors. The active cavity was divided into three regions according to the properties of the amino acids surrounded and was used for the docking of 16 known active inhibitors. Four accurate docking methods were employed to analyze the ligand-protein interactions in our molecular simulation study. Combining pharmacophore model with docking results, an interaction model was obtained with four features that were consistent with one another, which was more powerful in illuminating the binding site. The research elucidated a valuable relationship between structure and activity, at the same time it proposed an accurate binding model that was instructive in the development of novel and potent Nav1.7 inhibitors in the future.
Keywords: Molecular docking; Nav1.7; Pain; Pharmacophore models; Structure activity relationship.
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