3D Pharmacophore-based Virtual Screening, Docking Approaches toward the Discovery of Novel HPPD Inhibitors

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 compound showed remarkable ability to retrieve known active ligands from decoy molecule. 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. 4 Compounds with top rank in HipHop model and well-known binding model were finally chosen as identification of lead compounds with potentially inhibitory effects on active site of target. The results provided powerful insight to the development of novel HPPD inhibitors herbicides using computational techniques.

Herbicidal activity of isobenzofuranones and in silico identification of their enzyme target

“…Therefore, several researchers are using computational chemistry to speed up the process and reduce the cost of development . Among the several in silico methods available it is worth mentioning the docking and pharmacophore methods, which can be used to reveal interactions between phytotoxic compounds and their enzyme targets …”

“…21 Among the several in silico methods available it is worth mentioning the docking and pharmacophore methods, which can be used to reveal interactions between phytotoxic compounds and their enzyme targets. 22 Motivated by the biological activity described in the literature for natural isobenzofuranones this work was aimed at evaluating the phytotoxic activity of the , -unsaturated lactone 6, the tetrahydroisobenzofuran-1(3H)-ones (7 and 8) and the hexahydroisobenzofuran-1(3H)-ones (9-13, 14a, 14b, 15a, 15b and 16-20) in seeds of Cucumis sativus L. (cucumber), Sorghum bicolor L. Moench (sorghum), and Allium cepa L. (onion). These cultures were chosen due to the good response in short time when in contact with active principle even at low concentration.…”

Synthesis and herbicidal activity of novel pyrazole aromatic ketone analogs as HPPD inhibitor

“…The molecular docking simulations were conducted using Discovery Studio 2.5 software according to the reported method. [48][49][50] As its close pyrazole HPPD analogues, the proherbicides pyrazolynate and pyrazoxyfen were metabolized in vivo to the biologically active HPPD inhibitors 4-(2,4-dichlorobenzoyl)-1,3-dimethyl-5-hydroxypyrazole in plants, 51 so the chemical structure of the intermediate (3-(2-(4-chlorophenoxy)ethoxy)-2-methyl-4-(methylsulfonyl) phenyl)(5-hydroxy-1,3-dimethyl-1H-pyrazol-4-yl)methanone 9 was selected as ligand and drawn in the Discovery Studio 2.5 software. The AtHPPD structure (PDB code: 1TFZ) was selected for docking simulation and binding sites were generated from the protein complex.…”

Combining CBP Pharmacophore Construction and Molecular Docking to Search for Potential Competitive Inhibitors of Chitin Deacetylase

“…The use of computational techniques in drug discovery and development has become the most effective method. Ligand-based virtual screening of drugs can efficiently screen potential compounds from a large number of compounds through the interaction between proteins and small molecule compounds, avoiding blind screening, thereby reducing human, financial and time costs [16]. This study will use DS2016 software to further explore competitive inhibitors of chitin deacetylase on the basis of docking acetate and other molecules with chitin deacetylase.…”