Identification of novel HPPD/PPO dual-target inhibitors through virtual screening of multiple pharmacophore models.

Abstract

The development and identification of dual target herbicides was one of primary approach to addressing the issue of weed resistance. Protoporphyrinogen oxidase (PPO) and p-hydroxyphenylpyruvate dioxygenase (HPPD) are two important targets of photosynthesis in plants. Different from the traditional single target drug design, this study focuses on HPPD and PPO dual target drug design. Hiphop pharmacophore models of HPPD and PPO targets were constructed use commercial pesticides, and CBP pharmacophore models were constructed based on protein complexes. Over millions of molecules were screened using pharmacophore models and 8 compounds were obtained. Candidate compounds chelated with Fe (II) in HPPD and formed stable π-π interactions with key residues in HPPD active pocket. Most compounds produced hydrogen bond interactions and π-π interactions with residues in PPO. Combined with a multiple visual screen process, potential compounds with dual-target inhibition effect were obtained.