Molecular insight into the inhibition mechanism of plant and rat 4-hydroxyphenylpyruvate dioxygenase by molecular docking and DFT calculations

The 4-hydroxyphenylpyruvate dioxygenase (HPPD) is a relevant target protein for therapeutic and agrochemical research. It is an iron-dependent enzyme, and its inhibition has very different effects on plants and animals. In animals, the enzyme has an important role in the catabolism of tyrosine, and in the plant, it operates in the cascade of photosynthesis. Potent HPPD inhibitors have been described, and all contain the 1,3-diketone group in its shape. In this research, we carried out a study of the interaction modes of HPPD enzymes from plant and rat with selective and non-selective herbicides which already available with their structures to identify the molecule groups which are essential to their activity and those that are likely to changes, mediated by molecular computations. In this theoretical investigation, methods of molecular docking, reaction mechanism (QM/MM) and AIM calculations were employed, aiming the search for new more active and selective herbicides. Modifications were performed for DAS 645 and DAS 869 inhibitors. DAS 645 presented a good selectivity for the inhibition of the plant enzyme, and the modifications to the analogs design done increased its activity. For this compound, π–π* stacking interactions seem to be important, and this fact was proven by using AIM calculations. The other prototype compound, DAS 869, a potent inhibitor for both enzymes, had its increased activity in the plant and rat enzyme after added groups capable of performing π–π* stacking interactions.