Abstract
Yellow fever (YF), a mosquito-borne viral haemorrhagic fever, is one of the most lethal viral diseases. Despite the availability of vaccines, yellow fever virus (YFV) strikes an estimated 2, 00,000 persons world-wide each year and causes 30,000 deaths approximately. There are no approved antiviral therapies for the treatment of YFV disease in humans. YFV 17D strain RNA genome is of 10,862 nucleotides, which encodes three structural proteins (C, PrM, and E) and seven nonstructural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). Identification of different protein functions facilitates a mechanistic understanding of YFV infection and opens novel means for drug development. Functional assignment of complete YFV proteome was done through support Vector machine (SVM). Significant functions of YFV Envelope (E) protein are Transmembrane, Aptamer-binding protein, Coat protein, Zinc-binding, Manganese-binding and Metal-binding etc. The E protein being non homologous to human and important in receptor binding, hemagglutination of erythrocytes at acidic pH, induction of the protective immune response, and involvement in an intraendosomal acid-catalyzed fusion step necessary for infection was selected as a potent molecular target against YFV drug discovery. 3D structure of target protein E protein is predicted using MODELLER9V6 and validated through PROCHECK analysis. The Binding site tool of Discovery Studio 2.0 was used to find sites all over protein. Heparin was identified as an important ligand against the molecular target and was docked to the functionally important binding site using LigandFit protocol. The YFV E protein -Heparin docking complex associated with strong hydrogen bonding with SER 483, GLN 443 and ALA 441 residues. The strong docking interaction may impede the infection causes due to association of YFV E protein and Core membrane. Further, the predicted model can be used as reference towards designing candidate drugs against YFV.
Highlights
Functional assignment of complete yellow fever virus (YFV) 17D proteome was done through support Vector machine (SVM) (Sahoo et al 2008)
The YFV 17D E protein being non-homologous to human, we propose it as molecular target for structure based drug discovery (SBDD) against YFV 17D. 3D structure of YFV 17D E protein was built based on crystal structure of Dengue virus 2 Major envelope protein in MODELLER9V7 (Sahoo et al, 2009)
Six selected lead molecules were docked to functionally important binding site of YFV 17D E protein using LigandFit (Sahoo et al, 2009) module of Discovery Studio 2.0
Summary
The envelope (E) protein is the major structural protein of YFV17D and is understood to mediate several important virus functions such as host cell receptor-binding, membrane fusion activity and virion assembly (Heinz & Mandl, 1993). 3D structure of YFV 17D E protein was built based on crystal structure of Dengue virus 2 Major envelope protein in MODELLER9V7 (Sahoo et al, 2009). Six selected lead molecules were docked to functionally important binding site of YFV 17D E protein using LigandFit (Sahoo et al, 2009) module of Discovery Studio 2.0.
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