Aryloxyacetic acid derivatives as inhibitors of the HPPD enzyme: A quantitative structure-activity relationship analysis

The present work involved a quantitative analysis of the inhibitory effects of aryloxyacetic acid derivatives against Arabidopsis thaliana 4-hydroxyphenylpyruvate dioxygenase (AtHPPD). The study is an important in silico approach to design potential inhibitors of AtHPPD on rational basis. Also, it is helpful to optimize the existing leads to improve their biological activities and to predict the biological activities of untested and sometimes yet unavailable compounds. Moreover, the study could assist to decipher the possible mechanism of action on to receptor site(s) at the molecular level. The rational approach minimizes the time and cost needed in the drug designing process in comparison to traditional drug discovery methods. A total of 51 compounds were examined for the inhibition actions in relation to their molecular structures. The investigation revealed 15 prominent regression models, sharing 20 chemometric descriptors. Each of these models was validated for its internal and external robustness, while the randomization test was performed to avoid any coincidental correlation. The importance of these descriptors was further elaborated through the partial least squares analysis. The highest significant model was employed to calculate/predict the inhibition activities of all analogs of the series. The applicability domain analysis suggested that the model, under consideration, has satisfactory predictability. The guidelines given in the discussion may be helpful in exploring new potential analogs of the series.