In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors

Jason G. Glanzer, Brendan M. Byrne, Aaron M. McCoy, Ben J. James, Joshua D. Frank, Greg G. Oakley

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Ebola virus continues to be problematic as sporadic outbreaks in Africa continue to arise, and as terrorist organizations have considered the virus for bioterrorism use. Several proteins within the virus have been targeted for antiviral chemotherapy, including VP35, a dsRNA binding protein that promotes viral replication, protects dsRNA from degradation, and prevents detection of the viral genome by immune complexes. To augment the scope of our antiviral research, we have now employed molecular modeling techniques to enrich the population of compounds for further testing in vitro. In the initial docking of a static VP35 structure with an 80,000 compound library, 40 compounds were selected, of which four compounds inhibited VP35 with IC50<200 μM, with the best compounds having an IC50of 20 μM. By superimposing 26 VP35 structures, we determined four aspartic acid residues were highly flexible and the docking was repeated under flexible parameters. Of 14 compounds chosen for testing, five compounds inhibited VP35 with IC50<200 μM and one compound with an IC50of 4 μM. These studies demonstrate the value of docking in silico for enriching compounds for testing in vitro, and specifically using multiple structures as a guide for detecting flexibility and provide a foundation for further development of small molecule inhibitors directed towards VP35.

Original languageEnglish (US)
Pages (from-to)5388-5392
Number of pages5
JournalBioorganic and Medicinal Chemistry
Volume24
Issue number21
DOIs
StatePublished - 2016

Keywords

  • Ebola
  • Inhibitor
  • Innate immune response
  • Molecular dynamic modeling
  • VP35

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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