DFT-Based QSAR Study of Toxicity of 2-(2,4-dichlorophenoxy)propanoic acid and 2-(3,4-dichlorophenoxy)propanoic acid Compounds

In modern drug discovery process, ADME/Tox (absorption, distribution, metabolism, excretion, along with toxicity) properties should be determined as early as possible in the test cascade to allow a timely assessment of their property profiles [1]. Among ADME/Tox properties, drug metabolism is a key determinant of several important drug processes in vivo, such as metabolic stability, drug–drug interactions and drug toxicity [2]. Many physiological activities of molecules can be related to their composition and structures. Molecular descriptors, which are the numerical representation of the molecular structures, are used to perform Quantitative structure activity relationships (QSAR) analysis. Therefore, the DFT method is expected to lead to statistically more accurate QSAR model by comparing the semi-empirical methods. Aim of the present study is QSAR study to explore the correlations between activity and calculated molecular descriptors of 2-(2,4-dichlorophenoxy)propanoic acid and 2-(3,4-dichlorophenoxy)propanoic acid compounds. The ground state geometries of these compounds have been optimized by using density functional theory (DFT) at B3LYP/6-311G level of theory. We evaluated the overall predictive capacity of the models for the training set compounds and model derived predictions for the test set compounds. The computed properties of investigated compounds have been compared as well as available experimental data. The results also suggest that number and position of the substituents plays a dominant role in describing the toxicity. However, electronic factors are also important for the predictability of the models. The models built in the present study can be used for the prediction of toxicity of untested aldehydes against . The model based on factors scores of descriptors of different bonds was able to identify the important fragment responsible for the mediation of toxicity of 2-(2,4-dichlorophenoxy)propanoic acid and 2-(3,4-dichlorophenoxy)propanoic acid as corroborated by their established mechanism of toxicity. 2-(2,4-dichlorophenoxy)propanoic acid 2-(3,4-dichlorophenoxy)propanoic acid [Scheme]