3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors.

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

doi:10.3390/molecules22060959

Abstract

p-Hydroxyphenylpyruvate dioxygenase (HPPD) is not only the useful molecular target in treating life-threatening tyrosinemia type I, but also an important target for chemical herbicides. A combined in silico structure-based pharmacophore and molecular docking-based virtual screening were performed to identify novel potential HPPD inhibitors. The complex-based pharmacophore model (CBP) with 0.721 of ROC used for screening compounds showed remarkable ability to retrieve known active ligands from among decoy molecules. The ChemDiv database was screened using CBP-Hypo2 as a 3D query, and the best-fit hits subjected to molecular docking with two methods of LibDock and CDOCKER in Accelrys Discovery Studio 2.5 (DS 2.5) to discern interactions with key residues at the active site of HPPD. Four compounds with top rankings in the HipHop model and well-known binding model were finally chosen as lead compounds with potential inhibitory effects on the active site of target. The results provided powerful insight into the development of novel HPPD inhibitors herbicides using computational techniques.

Highlights

Weeds compete with crops for sunshine, water, nutrients, and space, which influences the growth of crops and undermines both crop quality and yield
As an important enzyme correlated to the pigment synthesis and tyrosine catabolism in most organisms, Hydroxyphenylpyruvate dioxygenase (HPPD) is important in drug discovery in both agricultural and therapeutic areas [3,4,5]
DSA869was wasused usedasasa virtual a virtual thatwas wasgenerated generatedbased basedon on protein protein 1TFZ and complex-based pharmacophore model (CBP) that was generated based on protein 1TFZ and inhibitor DSA869 was used as a virtual screening model discoverynovel novelHPPD

Summary

Introduction

Weeds compete with crops for sunshine, water, nutrients, and space, which influences the growth of crops and undermines both crop quality and yield. The discovery of novel high-activity and low-toxicity herbicide lead compounds still remains a challenge. HPPD catalyzes the conversion of 4-hydroxyphenylpyruvate (HPPA) to homogentisate (HGA), and this transformation involving decarboxylation, aromatic hydroxylation, and substituent migration in a single catalytic cycle is unique in Nature [6]. HGA can be further transformed into tocopherol and plastoquinone, both of them are crucial for the normal growth of plants [7]. Inhibition of HPPD will block photosynthesis, which leads to the deficiency in isoprenoid redox cofactors such as plastoquinone and tocopherol, and causes growth inhibition, necrosis and death of treated plants [8,9,10,11]

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