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Research Journal of Pharmacy and Technology
Year : 2020, Volume : 13, Issue : 7
First page : ( 3129) Last page : ( 3134)
Print ISSN : 0974-3618. Online ISSN : 0974-360X.
Article DOI : 10.5958/0974-360X.2020.00553.3

Structure-based Pharmacophore Modelling for identifying VEGFR2 Inhibitor

Arba Muhammad*, Jasriati Jasriati

Faculty of Pharmacy, Universitas Halu Oleo, Kendari, Indonesia-93231

*Corresponding Author E-mail: muh.arba@uho.ac.id

Online published on 10 August, 2020.

Abstract

The vascular endothelial growth factor (VEGF) plays a crucial role in a wide range of cellular functions particularly in the angiogenesis process. Overexpression of vascular endothelial growth factor receptor (VEGFR) leads to several disease including cancer. Inhibition of the VEGFR constitutes the major strategies for combating cancer growth. The current investigation was aimed at identifying potential inhibitor of VEGFR2 by using structure-based pharmacophore modelling using LigandScout 4.3. Advanced software. The pharmacophore hypothesis consisted of 4 hydrophobic, one hydrogen bond donor, and two hydrogen bond acceptors, which was built using the structure of cognate ligand of VEGFR2 (608). Further, the pharmacophore model was used to screen hit molecule against ZINC database using Pharmit. Further, 102 virtual hits were retrieved, which were submitted to molecular docking simulation by employing iDock software. Molecular dynamics simulation of 50 ns for each three best hits complexed with VEGFR2 indicated that each ligand underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Prediction of affinities employing Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) method identified one hit molecule (i.e. Lig5/ZINC33025328) with significant affinity lower than that of cognate ligand, which indicated its potential as a novel VEGFR2 inhibitor.

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Keywords

VEGFR2, molecular dynamics simulation, virtual screening, pharmacophore model, Ligand Scout.

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