Abstract
4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a significant enzyme in the biosynthesis of plastoquinone and tocopherol. Moreover, it is also a potential target to develop new herbicide. The technology of computer-aided drug design (CADD) is a useful tool in the efficient discovery of new HPPD inhibitors. Forty-three compounds with known activities were used to generate comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models based on common framework and molecular docking. The structural contribution to the activity was determined, which provided further information for the design of novel inhibitors. Molecular docking was used to explain the changes in activity caused by the binding mode between ligand and protein. The molecular dynamics (MD) results indicated that the electrostatic energy was the major driving force for ligand–protein interaction and the Phe403 made the greatest contribution to the binding. The present work has provided useful information for the rational design of novel HPPD inhibitors with improved activity.
Highlights
4-Hydroxyphenylpyruvate dioxygenase (HPPD), a Fe(II)-dependent non-heme oxygenase, belongs to the α-ketoacid family and plays different roles in organism and plant cells (Rocaboy-Faquet et al, 2014; Huang et al, 2016)
The comparative molecular field analysis (CoMFA) model based on molecular docking was built with Q2 = 0.693 and R2 = 0.998, and at this time, the ONC value was 10; the standard error of estimate (SEE) value of 0.034, the F value of 898.323, and the R2pred value of 0.828 were obtained
The steric field result from common framework is shown in Figure 5A; the green color represented that the bulky group was favorable to the bioactivity of the HPPD inhibitors
Summary
4-Hydroxyphenylpyruvate dioxygenase (HPPD), a Fe(II)-dependent non-heme oxygenase, belongs to the α-ketoacid family and plays different roles in organism and plant cells (Rocaboy-Faquet et al, 2014; Huang et al, 2016). It catalyzes the conversion of 4-hydroxyphenylpyruvate (HPPA) into homogentisate (HGA), which is the first committed metabolism of the tyrosine catabolism pathway in humans (Raspail et al, 2011; Moran, 2014; Silva et al, 2015). HPPD has been the subject as an important target for development of new herbicides and multiple series of compounds have been designed and synthesized (Wang et al, 2014, 2015b; Ndikuryayo et al, 2019). The obtained information will contribute to the rational design of novel HPPD inhibitors with powerful activity in the future
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