Abstract
The search for small molecule inhibitors of Ebola virus (EBOV) has led to several high throughput screens over the past 3 years. These have identified a range of FDA-approved active pharmaceutical ingredients (APIs) with anti-EBOV activity in vitro and several of which are also active in a mouse infection model. There are millions of additional commercially-available molecules that could be screened for potential activities as anti-EBOV compounds. One way to prioritize compounds for testing is to generate computational models based on the high throughput screening data and then virtually screen compound libraries. In the current study, we have generated Bayesian machine learning models with viral pseudotype entry assay and the EBOV replication assay data. We have validated the models internally and externally. We have also used these models to computationally score the MicroSource library of drugs to select those likely to be potential inhibitors. Three of the highest scoring molecules that were not in the model training sets, quinacrine, pyronaridine and tilorone, were tested in vitro and had EC 50 values of 350, 420 and 230 nM, respectively. Pyronaridine is a component of a combination therapy for malaria that was recently approved by the European Medicines Agency, which may make it more readily accessible for clinical testing. Like other known antimalarial drugs active against EBOV, it shares the 4-aminoquinoline scaffold. Tilorone, is an investigational antiviral agent that has shown a broad array of biological activities including cell growth inhibition in cancer cells, antifibrotic properties, α7 nicotinic receptor agonist activity, radioprotective activity and activation of hypoxia inducible factor-1. Quinacrine is an antimalarial but also has use as an anthelmintic. Our results suggest data sets with less than 1,000 molecules can produce validated machine learning models that can in turn be utilized to identify novel EBOV inhibitors in vitro.
Highlights
In 2014, the outbreak of the Ebola virus (EBOV) in West Africa highlighted the need for broad-spectrum antiviral drugs for this and other emerging viruses[1]
We have previously summarized the numerous small molecules described in the literature as possessing antiviral activity that could be further evaluated for their potential EBOV activity alongside the few new antivirals
Some have suggested that G-protein-coupled receptors (GPCRs) may play a role in filoviral entry and receptor antagonists could be developed as anti-EBOV therapies[12]
Summary
In 2014, the outbreak of the Ebola virus (EBOV) in West Africa highlighted the need for broad-spectrum antiviral drugs for this and other emerging viruses[1]. We have found that there is considerable prior knowledge regarding these small molecules possessing activity against EBOV in vitro or in animal models[5,6,7,8], and this includes a number of accessible FDA-approved drugs[2,3,9] Another recent study has shown three approved ion channel blockers (amiodarone, dronedarone, and verapamil) inhibited EBOV cellular entry[9]. For example amodiaquine and chloroquine are well known antimalarials, clomiphene and toremifene are selective estrogen receptor modulators, while amiodarone, dronedarone, and verapamil are anti-arrhythmics[4] It may or may not be of importance but all of these compounds have a common tertiary amine feature[10,11].
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