Abstract
Ebola virus causes severe and often fatal hemorrhagic fevers in humans. The 2014 Ebola epidemic affected multiple countries. The virus matrix protein (VP40) plays a central role in virus assembly and budding. Since there is no FDA-approved vaccine or medicine against Ebola viral infection, discovering new compounds with different binding patterns against it is required. Therefore, we aim to identify small molecules that target the Arg 134 RNA binding and active site of VP40 protein. 1800 molecules were retrieved from PubChem compound database based on Structure Similarity and Conformers of pyrimidine-2, 4-dione. Molecular docking approach using Lamarckian Genetic Algorithm was carried out to find the potent inhibitors for VP40 based on calculated ligand-protein pairwise interaction energies. The grid maps representing the protein were calculated using auto grid and grid size was set to 60*60*60 points with grid spacing of 0.375 Ǻ. Ten independent docking runs were carried out for each ligand and results were clustered according to the 1.0 Ǻ RMSD criteria. The post-docking analysis showed that binding energies ranged from -8.87 to 0.6 Kcal/mol. We report 7 molecules, which showed promising ADMET results, LD-50, as well as H-bond interaction in the binding pocket. The small molecules discovered could act as potential inhibitors for VP40 and could interfere with virus assembly and budding process.
Highlights
Ebola virus (EBOV) is a member of Filoviridae virus family, which causes acute hemorrhagic fever with a high case-fatality rate in humans. in a recent outbreak in 2014, it affected Guinea, Liberia, and Sierra Leone, and Nigeria with high case fatality rates [1].EBOV is an enveloped, negative-sense RNA virus which encodes seven structural proteins within its 19kb linear genome including nucleoprotein (NP), VP35, VP40, VP30, VP24, polymerase (L) and membrane-anchored glycoprotein (GP) as well as the nonstructural secreted glycoprotein and small secreted glycoprotein [2]
EBOV strains consist of four different species: Zaire ebolavirus (ZEBOV), Sudan ebolavirus (SEBOV), Côte d’Ivoire ebolavirus (CIEBOV) and Reston ebolavirus (REBOV)
Figure 1 shows 3D of Crystal Structure of matrix protein VP40 from Ebola virus Sudan acquired from RCSB
Summary
Ebola virus (EBOV) is a member of Filoviridae virus family, which causes acute hemorrhagic fever with a high case-fatality rate in humans (up to 90%). in a recent outbreak in 2014, it affected Guinea, Liberia, and Sierra Leone, and Nigeria with high case fatality rates [1].EBOV is an enveloped, negative-sense RNA virus which encodes seven structural proteins within its 19kb linear genome including nucleoprotein (NP), VP35, VP40, VP30, VP24, polymerase (L) and membrane-anchored glycoprotein (GP) as well as the nonstructural secreted glycoprotein (sGP) and small secreted glycoprotein (ssGP) [2]. Ebola virus (EBOV) is a member of Filoviridae virus family, which causes acute hemorrhagic fever with a high case-fatality rate in humans (up to 90%). Biochemistry and cellular microscopy postulated that VP40 rearranges into different structures, each with a distinct function required for the ebolavirus life cycle [3]. The structure revealed that VP40 contains distinct N- and Cterminal domains, both are essential for trafficking to and interaction with the membrane. There, electrostatic interactions trigger rearrangement of the polypeptide into a linear hexamer. These hexamers construct a multi-layered, filamentous matrix structure that is critical for ISSN 0973-2063 (online) 0973-8894 (print) Bioinformation 12(3): 192-196 (2016)
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