Combination of Virtual Screening Protocol by in Silico toward the Discovery of Novel 4-Hydroxyphenylpyruvate Dioxygenase Inhibitors.

Ying Fu,Yi-Na Sun,Ke-Han Yi,Fei Ye,Ming-Qiang Li,Jia-Zhong Li,Hai-Feng Cao

doi:10.3389/fchem.2018.00014

Ying Fu, Yi-Na Sun + Show 5 more

Open Access

https://doi.org/10.3389/fchem.2018.00014

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Abstract

4-Hydroxyphenylpyruvate dioxygenase (EC 1.13.11.27, HPPD) is a potent new bleaching herbicide target. Therefore, in silico structure-based virtual screening was performed in order to speed up the identification of promising HPPD inhibitors. In this study, an integrated virtual screening protocol by combining 3D-pharmacophore model, molecular docking and molecular dynamics (MD) simulation was established to find novel HPPD inhibitors from four commercial databases. 3D-pharmacophore Hypo1 model was applied to efficiently narrow potential hits. The hit compounds were subsequently submitted to molecular docking studies, showing four compounds as potent inhibitor with the mechanism of the Fe(II) coordination and interaction with Phe360, Phe403, and Phe398. MD result demonstrated that nonpolar term of compound 3881 made great contributions to binding affinities. It showed an IC50 being 2.49 μM against AtHPPD in vitro. The results provided useful information for developing novel HPPD inhibitors, leading to further understanding of the interaction mechanism of HPPD inhibitors.

Highlights

The success probability for novel herbicides discovery in agricultural field is cutting down and weeds are becoming widely resistant to most common used herbicide in recent years (Green, 2014), all these make weed management difficult and time consuming
The best quantitative pharmacophore models indicated that Hydrogen bond acceptor (HBA), hydrogen bond donor (HBD), HA and ring aromatic (RA) features were important
The cost difference 122.85 between null and fixed cost was more than 70 bits, which illustrated that total cost was far from the null cost

Summary

Introduction

The success probability for novel herbicides discovery in agricultural field is cutting down and weeds are becoming widely resistant to most common used herbicide in recent years (Green, 2014), all these make weed management difficult and time consuming. There is an urgent need for novel herbicide discovery to overcome the weeds resistance. The 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor offers such solutions by bleaching herbicide mode of action. HPPD catalyzes the conversion of p-hydroxyphenylpyruvate (HPPA) to homogentisate (HGA) in aerobic metabolism. This reaction involves decarboxylation, substituent migration and aromatic oxygenation in a single catalytic cycle (Moran, 2005; Purpero and Moran, 2006).

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