Our latest contribution to the Ebola literature came out today. A collaboration with Peter Madrid (SRI International), Robert Davey and Manu Anantpadma (Texas Biomedical Research Institute), Alex Clark (Molecular Materials Informatics) and Joel Freundlich (Rutgers).
Last year I posted a few times on Ebola here, here here and here. This interest all stemmed from some Tweets shared with Chris Southan and Megan Coffee. This in turn lead to a little work on the antimalarials and SERMs that came out of the earliest HTS screens to try to identify a target. I told most of the story at the ACS a few months ago.
Well to summarize, I initially reached out to Peter Madrid to access his HTS data from screening a library against Ebola in vitro. He had some unpublished data to add as well. This enabled me to build some Bayesian models and do some compound library searching. Joel kindly interpreted the features in the active and inactive molecules. Initially this work was going to be a part of the pharmacophore paper, but it was held out so that Peter could get some data out. This was ideal because I started to put a draft together for the ISCB competition, by this point I had also reached out to Robert Davey. I had picked 3 compounds that scored well (got Joel’s blessing) and were not in the training set. Peter purchased the compounds and Manu and Robert kindly tested them. During this time I had also looked at model building with other software/ algorithms and with Alex’s help made the models available for use with mobile apps. Initial in vitro results looked good and were available before the ACS presentation and since then addition in vitro work provided more confidence. The bottom line was we were able to find 3 compounds with activity in the hundreds of nM range. Interestingly 2 of these compounds were also identified as part of the earlier pharmacophore work for VP35. What is interesting is the 3 compounds have not been identified previously. Pyronaridine is used as part of an antimalarial combination drug. Quinacrine is an old antimalarial and anthelmintic while Tilorone is is an investigational antiviral with broad biological activity.
The next step is trying to get the compounds tested in the in vivo model of Ebola infection. It is hard to believe its taken a year to get to this point, and still people are dying from Ebola in Africa. I hope we can get further and provide some hope.