Virtual Screening and Bioassay of Novel Protoporphyrinogen Oxidase and -Hydroxyphenylpyruvate Dioxygenase Dual-Target Inhibitors.

Novel herbicide development is a challenge for weed control. Protoporphyrinogen oxidase (PPO) and -hydroxyphenylpyruvate dioxygenase (HPPD) are two key enzymes involved in plant photosynthesis. The multi virtual screening protocol was adopted to design a common skeleton based on the two target enzymes, and fragment growth of the skeleton was performed. The constructed compounds were searched for structural similarity, and the accuracy of the selected compounds was further verified using the Bayesian model. Finally, eight compounds were obtained, and the binding mode with the target was studied deeply. The obtained compounds interact with the key residues of HPPD and PPO proteins similarly to commercial herbicides, and the stability of binding with proteins is also good. The activity of the screening results was determined by an enzyme activity test in vitro. The herbicidal effect of the compound was studied by phenotypic experiment. The final results showed that Z-4 and Z-7 have the potential to become new dual-target herbicides.