Abstract:
Toluene is a commonly used organic solvent in commercial products and is sometimes, abused as an inhalative hallucinogen, causing arrythmogenic toxicity. At a molecular level we, investigated whether a hypothetical interaction model could be devised for the reported myoand, cardiotoxic effects of toluene. Three lines of computed evidence support our hypothesis, on the interaction mechanism: (i) Toluene binds at the local anesthetic binding site (LABS), on, the wild type (WT) but not on its F1579A mutation, confi rming our experimental fi ndings that, it inhibits only the WT of skeletal muscle or cardiac isoforms (Nav 1.4 or 1.5). (ii) Typically, for small alkylaryl moiety, multiple binding modes were detected during docking. Toluene is, trapped in the tryptophane-rich area at the extracellular vestibule by hydrophobic interaction, mainly π–π stacking, or bound to the LABS with equal binding strength and number of solved, poses, mostly by edge-to-face contacts. (iii) The computed loss of toluene binding at the LABS, on the mutant model parallels clearly the observed loss of toluene effects on Nav 1.4. Moreover, we inspected the complete primary sequences with the omitted loops in the 3D models to identify, the possible interacting amino acids among the 16% nonidentical ones, and thus confi rmed the, observed toxicity effects.