title: In silico prediction of ebolavirus RNA polymerase inhibition by specific combinations of approved nucleotide analogues.
abstract: OBJECTIVE
  The urgency of ebolavirus drug development is obvious in light of the current local epidemic in Western Africa with high morbidity and a risk of wider spread. We present an in silico study as a first step to identify inhibitors of ebolavirus polymerase activity based on approved antiviral nucleotide analogues.
  
  
  METHODS
  Since a structure model of the ebolavirus polymerase is lacking, we performed combined homology and ab initio modeling and report a similarity to known polymerases of human enterovirus, bovine diarrhea virus and foot-and-mouth disease virus. This facilitated the localization of a nucleotide binding domain in the ebolavirus polymerase. We next performed molecular docking studies with nucleotides (ATP, CTP, GTP and UTP) and nucleotide analogues, including a variety of approved antiviral drugs.
  
  
  CONCLUSIONS
  Specific combinations of nucleotide analogues significantly reduce the ligand-protein interaction energies of the ebolavirus polymerase for natural nucleotides. Any nucleotide analogue on its own did not reduce ligand-protein interaction energies. This prediction encourages specific drug testing efforts and guides future strategies to inhibit ebolavirus replication.
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: f.j.vanhemert@amc.uva.nl.
authors.forename: Formijn J
authors.initials: FJ
authors.lastname: van Hemert
authors.affiliation: Laboratory of Clinical Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: h.l.zaaijer@amc.uva.nl.
authors.forename: Hans L
authors.initials: HL
authors.lastname: Zaaijer
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. Electronic address: b.berkhout@amc.uva.nl.
authors.forename: Ben
authors.initials: B
authors.lastname: Berkhout
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D002417:Cattle; D003198:Computer Simulation; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D029043:Ebolavirus / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D062105:Molecular Docking Simulation; D009711:Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D010802:Phylogeny; D040681:Structural Homology, Protein
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009711:Nucleotides; D012321:DNA-Directed RNA Polymerases
keywords: Binding affinity; Ebolavirus; Modeling; Nucleotide analogues; Polymerase