Interpretation of toxicological activity of ionic liquids to acetylcholinesterase inhibition via in silico modelling

For designing environmentally friendly ionic liquids (ILs), their structural effects on the toxicity should be interpreted via modelling based on the quantitative-structure-activity-relationship (QSAR) concept. For the purpose, QSAR models for predicting IL toxicity in acetylcholinesterase activity were developed by using linear free-energy relationship (LFER) descriptors, whose chemical meanings are well defined. These are excess molar refraction (E_{c or a}), dipolarity/polarizability (S_{c or a}), H-bonding acidity (A_{c or a}), H-bonding basicity (B_{c or a}), McGowan volume (V_{c or a}), and ionic interactions of cation (J⁺) and anion (J^-). Since the experimentally determined LFER descriptors are not available, we calculated them based on density functional theory, conductor-like screening model and the open-source software, obprop. The toxicity values of imidazolium- and pyridinium-based ILs could be predicted by a combination of four descriptors (A_c, B_c, V_c and S_a) with an R² of 0.828, and (E_c, A_c, E_a and S_a) with an R² of 0.879, respectively. In prediction study using the overall dataset containing various IL structures, the six calculated terms (E_c, S_c, A_c, J⁺, E_a, and S_a) were selected and correlated with the observed toxicity values in R² of 0.748 for the training set, R² of 0.711 for the test set and R² of 0.655 for external validation set. And this study explains how the selected terms are contributing to the prediction models, and their chemical meanings were understood.