Making it open – putting cheminformatics to use against the Ebola virus

In 2014 Africa faced the most severe Ebola Virus epidemic to date. With no treatment in sight, limited knowledge of the virus and prompted by discussions on Twitter, I set about to see how much could be done without a lab to test compounds. In the past couple of years there have been multiple high throughput screens in an effort to find compounds active against the Ebola Virus, the challenge however, is that for most molecules the mechanism or a target is unknown. I focused initially on two antimalarials (amodiaquine and chloroquine) and two selective estrogen receptor modulators (clomiphene and toremifene). I used several cheminformatics approaches to propose a common pharmacophore, receptor-based pharmacophores and docking. Several database searches with the pharmacophores were made available on FigShare and eventually led to a paper on the work. With collaborators we also summarized what could be done for future outbreaks as well as highlighted that FDA approved drugs were apparently active at physiologically relevant concentrations. In addition we curated a literature dataset of compounds shown to be active in vitro or in vivo against the Ebola Virus and used an experienced medicinal chemist to evaluate the molecules. Most recently two-pore channels were shown as key for viral entry into host cells and seven small molecules tested as inhibitors of infection. These molecules were used to create a common feature pharmacophore that was compared with the previously published pharmacophore, suggesting the 4 compounds may also be targeting this channel. Searching the literature dataset with the two-pore channel pharmacophore suggested additional molecules that might share the same mechanism. To date this cheminformatics work has resulted in 4 manuscripts published in F1000Research as well as data and models that have been shared openly.