Quantitative structure toxicity analysis of ionic liquids toward acetylcholinesterase enzyme using novel QSTR models with index of ideality of correlation and correlation contradiction index

Abstract

Ionic liquids (ILs) have enticed the curiosity of chemists due to their vast applications in academic and industrial research. These have many advantages over other conventional solvents such as broad liquid temperature, negligible vapour pressure, non-volatility, etc. But, from an environmental point of view, these advantages can develop heterogeneous toxic results when released into the environment. It is important to predict the toxicity of ionic liquids. A useful tool for predicting ILs toxicity is the quantitative structure-toxicity relationship (QSTR). The toxicity of ionic liquids is evaluated by predicting the acetylcholinesterase (AChE, EC3.1.1.7) enzyme inhibition. In the present manuscript, an exhaustive QSTR analysis for 229 ionic liquids as an acetylcholinesterase enzyme inhibitor is described using the inbuilt Monte Carlo optimization method of CORAL software. Eleven splits are prepared and from these split, 22 QSTR models are developed using two target functions, i.e. TF1 (without IIC) and TF2 (with IIC). All models developed by TF2 are robust and have better predictability. The model developed for split 1 using TF2 is considered as the best model (RValid2 = 0.7782). In the present work, a novel parameter “Correlation Contradiction Index (CCI)” is studied to recognize its predictability. The docking simulation was also performed to understand the mechanistic interpretation. Further, the mechanistic interpretation of the best QSTR model was in good correlation with the three-dimensional studies of ligand binding. In order to see the true picture of inhibitory potential, ligand transport study of five ILs (IL015, IL040, IL116, IL156 and IL211) was studied in the tunnel leading to the active site of AChE using the services of Caver Web. Result of the transport study showed that these ILs formed a most stable complex in the active site and not in the tunnel and did not obstruct the tunnel for the accessibility of the enzyme active site for the substrate.