title: Drug repurposing to target Ebola virus replication and virulence using structural systems pharmacology.
abstract: BACKGROUND
  The recent outbreak of Ebola has been cited as the largest in history. Despite this global health crisis, few drugs are available to efficiently treat Ebola infections. Drug repurposing provides a potentially efficient solution to accelerating the development of therapeutic approaches in response to Ebola outbreak. To identify such candidates, we use an integrated structural systems pharmacology pipeline which combines proteome-scale ligand binding site comparison, protein-ligand docking, and Molecular Dynamics (MD) simulation.
  
  
  RESULTS
  One thousand seven hundred and sixty-six FDA-approved drugs and 259 experimental drugs were screened to identify those with the potential to inhibit the replication and virulence of Ebola, and to determine the binding modes with their respective targets. Initial screening has identified a number of promising hits. Notably, Indinavir; an HIV protease inhibitor, may be effective in reducing the virulence of Ebola. Additionally, an antifungal (Sinefungin) and several anti-viral drugs (e.g. Maraviroc, Abacavir, Telbivudine, and Cidofovir) may inhibit Ebola RNA-directed RNA polymerase through targeting the MTase domain.
  
  
  CONCLUSIONS
  Identification of safe drug candidates is a crucial first step toward the determination of timely and effective therapeutic approaches to address and mitigate the impact of the Ebola global crisis and future outbreaks of pathogenic diseases. Further in vitro and in vivo testing to evaluate the anti-Ebola activity of these drugs is warranted.
authors.affiliation: High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, P. R. China.|National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: The Graduate Center, The City University of New York, New York, USA.
authors.forename: Che
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Chemistry, Hunter College, The City University of New York, New York, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Fan
authors.affiliation: Office of the Director, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Bourne
authors.affiliation: The Graduate Center, The City University of New York, New York, USA. lxie@iscb.org.|Department of Computer Science, Hunter College, The City University of New York, New York, USA. lxie@iscb.org.
authors.forename: Lei
authors.initials: L
authors.lastname: Xie
mesh_terms: D004261:DNA Replication; D058492:Drug Repositioning / Q000379:methods*; D029043:Ebolavirus / Q000254:growth & development*; D006801:Humans; D014774:Virulence; D014779:Virus Replication / Q000187:drug effects*