In silico investigation of novel arylthioacetic acid derivatives as inhibitors of the 4-hydroxyphenylpyruvate dioxygenase

Abstract

This study investigates the inhibitory potential of arylthioacetic acid derivatives against 4-hydroxyphenylpyruvate dioxygenase from Arabidopsis thaliana (AtHPPD) using in silico methods. The goal is to design and optimize potential AtHPPD inhibitors through QSAR modeling and molecular analyses. These computational approaches provide a cost-effective and time-efficient alternative to traditional drug discovery, enabling the prediction of biological activity for untested compounds.

       A dataset of sixty-nine arylthioacetic acid derivatives was analyzed to develop five significant regression models using eleven chemometric molecular descriptors. Model robustness was validated through internal checks and randomization tests. Partial least-squares (PLS) analysis highlighted the importance of the descriptors. The best model was used to predict the activities of additional analogues, and applicability domain analysis confirmed its reliable performance. These findings offer insights for identifying and designing new potent analogues in this chemical series.

       Furthermore, ADME-T (Absorption, Distribution, Metabolism, Excretion, and Toxicity) properties of the most active compounds were evaluated and compared with mesotrione, a commercially established HPPD-inhibiting herbicide. Three compounds (11, 40, and 49) were selected for detailed assessment. Similar to mesotrione, all three compounds satisfy Lipinski’s rule of five and exhibit favorable predicted human intestinal absorption. However, unlike mesotrione, they exhibit strong plasma protein binding. Toxicity predictions indicate that compounds 11 and 40 are non-carcinogenic in mice, whereas compound 49 shows carcinogenic potential. In rats, only compound 40 exhibits possible carcinogenicity, while compounds 11, 49, and mesotrione are predicted to be non-carcinogenic. Additionally, the compounds were classified as inhibitors or non-inhibitors of key cytochrome P450 enzymes, namely CYP2C19, CYP2D6, and CYP3A4.

       Molecular docking studies were performed on the most active compounds and compared with mesotrione to elucidate binding interactions within the AtHPPD active site. Notably, compound 49 exhibited a binding affinity comparable to mesotrione and demonstrated stronger intermolecular interactions, highlighting its potential as a promising lead candidate. Overall, this study provides valuable molecular insights and supports further exploration of arylthioacetic acid derivatives as potent AtHPPD inhibitors.