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

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...

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Autores principales: Fu, Ying, Sun, Yi-Na, Yi, Ke-Han, Li, Ming-Qiang, Cao, Hai-Feng, Li, Jia-Zhong, Ye, Fei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152767/
https://www.ncbi.nlm.nih.gov/pubmed/28598377
http://dx.doi.org/10.3390/molecules22060959
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author Fu, Ying
Sun, Yi-Na
Yi, Ke-Han
Li, Ming-Qiang
Cao, Hai-Feng
Li, Jia-Zhong
Ye, Fei
author_facet Fu, Ying
Sun, Yi-Na
Yi, Ke-Han
Li, Ming-Qiang
Cao, Hai-Feng
Li, Jia-Zhong
Ye, Fei
author_sort Fu, Ying
collection PubMed
description 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.
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spelling pubmed-61527672018-11-13 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors Fu, Ying Sun, Yi-Na Yi, Ke-Han Li, Ming-Qiang Cao, Hai-Feng Li, Jia-Zhong Ye, Fei Molecules Article 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. MDPI 2017-06-09 /pmc/articles/PMC6152767/ /pubmed/28598377 http://dx.doi.org/10.3390/molecules22060959 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fu, Ying
Sun, Yi-Na
Yi, Ke-Han
Li, Ming-Qiang
Cao, Hai-Feng
Li, Jia-Zhong
Ye, Fei
3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title_full 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title_fullStr 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title_full_unstemmed 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title_short 3D Pharmacophore-Based Virtual Screening and Docking Approaches toward the Discovery of Novel HPPD Inhibitors
title_sort 3d pharmacophore-based virtual screening and docking approaches toward the discovery of novel hppd inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152767/
https://www.ncbi.nlm.nih.gov/pubmed/28598377
http://dx.doi.org/10.3390/molecules22060959
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