title: Identification of novel target sites and an inhibitor of the dengue virus E protein.
abstract: Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound showed an IC(50) in the micromolar range against dengue virus type 2.
authors.affiliation: Centre for Computational Biology and Bioinformatics, School of Information Technology, Jawaharlal Nehru University, New Delhi, India.
authors.forename: Ragothaman
authors.initials: R
authors.lastname: Yennamalli
authors.forename: Naidu
authors.initials: N
authors.lastname: Subbarao
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kampmann
authors.forename: Ross P
authors.initials: RP
authors.lastname: McGeary
authors.forename: Paul R
authors.initials: PR
authors.lastname: Young
authors.forename: Bostjan
authors.initials: B
authors.lastname: Kobe
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D001665:Binding Sites; D003715:Dengue / Q000188:drug therapy* / Q000378:metabolism; D003716:Dengue Virus / Q000737:chemistry / Q000187:drug effects; D015195:Drug Design; D005416:Flavivirus / Q000737:chemistry / Q000187:drug effects; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics; D010948:Viral Plaque Assay
chemical_list: D000998:Antiviral Agents; C051821:E-glycoprotein, Dengue virus type 2; D014759:Viral Envelope Proteins; D014760:Viral Fusion Proteins