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Molecules 2016, 21(12), 1537; doi:10.3390/molecules21121537

Combating Ebola with Repurposed Therapeutics Using the CANDO Platform

1
Department of Chemistry; Purdue Institute for Drug Discovery; Purdue Institute for Inflammation, Immunology, and Infectious Disease; Purdue Institute for Integrative Neuroscience; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA
2
Department of Biomedical Informatics, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
3
Department of Internal Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY 14203, USA
*
Authors to whom correspondence should be addressed.
Academic Editor: Derek J. McPhee
Received: 29 July 2016 / Revised: 23 October 2016 / Accepted: 28 October 2016 / Published: 25 November 2016
(This article belongs to the Special Issue Drug Design and Discovery: Principles and Applications)
View Full-Text   |   Download PDF [1605 KB, uploaded 25 November 2016]   |  

Abstract

Ebola virus disease (EVD) is extremely virulent with an estimated mortality rate of up to 90%. However, the state-of-the-art treatment for EVD is limited to quarantine and supportive care. The 2014 Ebola epidemic in West Africa, the largest in history, is believed to have caused more than 11,000 fatalities. The countries worst affected are also among the poorest in the world. Given the complexities, time, and resources required for a novel drug development, finding efficient drug discovery pathways is going to be crucial in the fight against future outbreaks. We have developed a Computational Analysis of Novel Drug Opportunities (CANDO) platform based on the hypothesis that drugs function by interacting with multiple protein targets to create a molecular interaction signature that can be exploited for rapid therapeutic repurposing and discovery. We used the CANDO platform to identify and rank FDA-approved drug candidates that bind and inhibit all proteins encoded by the genomes of five different Ebola virus strains. Top ranking drug candidates for EVD treatment generated by CANDO were compared to in vitro screening studies against Ebola virus-like particles (VLPs) by Kouznetsova et al. and genetically engineered Ebola virus and cell viability studies by Johansen et al. to identify drug overlaps between the in virtuale and in vitro studies as putative treatments for future EVD outbreaks. Our results indicate that integrating computational docking predictions on a proteomic scale with results from in vitro screening studies may be used to select and prioritize compounds for further in vivo and clinical testing. This approach will significantly reduce the lead time, risk, cost, and resources required to determine efficacious therapies against future EVD outbreaks. View Full-Text
Keywords: drug repurposing and discovery; multitarget docking; compound–proteome interaction; candock drug repurposing and discovery; multitarget docking; compound–proteome interaction; candock
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Chopra, G.; Kaushik, S.; Elkin, P.L.; Samudrala, R. Combating Ebola with Repurposed Therapeutics Using the CANDO Platform. Molecules 2016, 21, 1537.

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