2D- and 3D-QSAR of Tocainide and Mexiletine analogues acting as Nav1.4 channel blockers

Enantiomeric forms of Tocainide, Mexiletine, and structurally related local anaesthetic compounds, were analyzed with respect to their potency in blocking Nav1.4 channel. Structure–activity relationships based on in vitro pharmacological assays, suggested that an increase in terms of lipophilicity and/or molecular surface as well as the presence of specific polar spacers might be determinant for receptor interactions. QSAR and pharmacophore models were then used to support at 3D level this hypothesis.

Graphical abstractCongruent 2D- and 3D-QSAR carried out a series of ion channel blockers are here reported together with a fresh pharmacophore hypothesis for this class of compounds. Interesting elements regarding the need for an efficient ion blocking activity emerged from this study.Figure optionsDownload full-size imageDownload as PowerPoint slide