Bridging the gap between molecular descriptors and mechanism: cases studies by molecular dynamics simulations

In recent years, both classification models and quantitative structure-activity relationships (QSARs) have been developed to discriminate the acute toxicity of polar narcotics and uncouplers. One of fundamental issues is how to select and interpret the molecular descriptors used in both methods. In this work, we first employed support vector machine on a dataset containing 155 polar narcotics and 19 uncouplers to filter the predictive hydrophobic and hydrogen bonding descriptors. Molecular dynamics simulations were then conducted to investigate the behavior of salicylate and pentachlorophenol molecules in the context of a palmitoyl-oleoyl-phosphatidylcholine lipid bilayer. The results demonstrated that their equilibrium properties in the lipid bilayer were closely associated with hydrophobic and hydrogen bonding descriptors. The preferable occupations of these molecules in the lipid bilayer were discussed in terms of their modes of toxic action. The observations from molecular dynamics simulations facilitated to elucidate the mechanism of polar narcotics and uncouplers.