Combating Ebola with Repurposed Therapeutics Using the CANDO Platform

被引:32
作者
Chopra, Gaurav [1 ,2 ,3 ,4 ,5 ]
Kaushik, Sashank [6 ,7 ]
Elkin, Peter L. [6 ,7 ]
Samudrala, Ram [6 ]
机构
[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA
[2] Purdue Univ, Purdue Inst Drug Discovery, W Lafayette, IN 47907 USA
[3] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA
[4] Purdue Univ, Purdue Inst Integrat Neurosci, W Lafayette, IN 47907 USA
[5] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA
[6] Univ Buffalo, Dept Biomed Informat, Jacobs Sch Med & Biomed Sci, Buffalo, NY 14203 USA
[7] Univ Buffalo, Jacobs Sch Med & Biomed Sci, Dept Internal Med, Buffalo, NY 14203 USA
来源
MOLECULES | 2016年 / 21卷 / 12期
关键词
drug repurposing and discovery; multitarget docking; compound-proteome interaction; candock; DRUG DISCOVERY; VIRUS; IDENTIFICATION; PATHOGENESIS; MODELS; ENTRY; TB;
D O I
10.3390/molecules21121537
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:11
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