Discovery of novel HPPD inhibitors based on a combination strategy of pharmacophore, consensus docking and molecular dynamics

4-Hydroxyphenylpyruvate dioxygenase (HPPD), an Fe(II)/Co(II)-dependent non-heme oxygenase, is a vital enzyme in the tyrosine catabolic pathway and has been proved to be a very successful herbicides target with bleaching properties. In this process, pharmacophore modeling combined with consensus docking was used to discover new HPPD-inhibitors. A total of 322,686 compounds from Targetmol, Bailingwei, and ZINC were screened through a multilayered screening work. To avoid the defects existing in the single docking process, the consensus docking was employed to analyze the docking results. Five compounds with good performance were finally obtained, and all of them could produce stable coordination with cobalt ions and form good pi-pi interactions. Calculated binding free energy indicated that the van der Waals (vdW), lipophilic, and coulomb force interactions were the major components to the binding affinity. The enzyme activity confirmed that Flavokawain A and Silymarin displayed significant potency against AtHPPD in vitro. This work provides a worthful theoretical basis and an important lead skeleton for the reasonable devise of innovative HPPD herbicides. (c) 2022 Elsevier B.V. All rights reserved.