In silico and in vitro methods to identify ebola virus VP35-dsRNA inhibitors
| Autor: | Joshua D. Frank, Brendan M. Byrne, Jason G. Glanzer, Ben J. James, Aaron M. McCoy, Greg G. Oakley |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
In silico Clinical Biochemistry Population Pharmaceutical Science Biology medicine.disease_cause Antiviral Agents Biochemistry Molecular Docking Simulation Article Virus Structure-Activity Relationship 03 medical and health sciences Drug Discovery medicine Computer Simulation education Molecular Biology education.field_of_study Ebola virus Dose-Response Relationship Drug Molecular Structure Viral Core Proteins Organic Chemistry Nucleocapsid Proteins Virology Nucleoprotein Nucleoproteins 030104 developmental biology Viral replication Docking (molecular) Molecular Medicine |
| Zdroj: | Bioorganic & Medicinal Chemistry. 24:5388-5392 |
| ISSN: | 0968-0896 |
| Popis: | 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 < 200uM, with the best compounds having an IC50 of 20 uM. 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 < 200uM and one compound with an IC50 of 4 uM. 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. |
| Databáze: | OpenAIRE |
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