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

• Published in: Molecules (Basel, Switzerland) Vol. 22; no. 6; p. 959
• Main Authors: Fu, Ying, Sun, Yi-Na, Yi, Ke-Han, Li, Ming-Qiang, Cao, Hai-Feng, Li, Jia-Zhong, Ye, Fei
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 09.06.2017; MDPI
• Subjects: 4-Hydroxyphenylpyruvate Dioxygenase - antagonists & inhibitors; 4-Hydroxyphenylpyruvate Dioxygenase - chemistry; Amino Acid Motifs; Catalytic Domain; Computer applications; Crystallography, X-Ray; Databases, Chemical; Drug Discovery; Enzyme Inhibitors - chemistry; Herbicides; Herbicides - chemistry; Hydrophobic and Hydrophilic Interactions; Hydroxyphenylpyruvate dioxygenase; Inhibitors; Kinetics; Lead compounds; Ligands; Molecular docking; Molecular Docking Simulation; Molecular structure; Organic chemistry; Pharmacology; Phenylpyruvic Acids - chemistry; Plant Proteins - antagonists & inhibitors; Plant Proteins - chemistry; Plant Weeds - chemistry; Plant Weeds - enzymology; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Protein Interaction Domains and Motifs; Quantitative Structure-Activity Relationship; Thermodynamics; User-Computer Interface; HPPD inhibitors; pharmacophore model; virtual screening; HipHop model; molecule docking; ChemDiv
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules22060959

-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.