This post provides an update of our CombiUgi project. From a larger perspective I think that this can be useful to people interested in how collaborative Open Science actually works. For those who have not been following the progress of the CombiUgi project on our mailing list, here is a brief update. The basic idea is to generate libraries of compounds that can be made quickly in the lab. The compounds in these virtual libraries are then prioritized according to potential usefulness (anti-malaria, anti-tumor, etc.). The top hits are then synthesized and tested. We chose the Ugi reaction because it is very simple experimentally - mix four components (an amine, an aldehyde, a carboxylic acid and an isonitrile) in methanol at room temperature. In the creation of the libraries we used only components that were commercially available. In our first library of 68,000 compounds, although all starting materials were commercially available, one of the main components needed (2-naphthyl isonitrile) for predicted anti-tumor activity was not available to ship for 6 weeks. Since it is important to keep this science loop as short as possible we reran the library generation with Rajarshi Guha's open web service using only compounds that were next-day shippable. We also used this opportunity to increase the number of compounds in the virtual library to 500,000. Rajarshi has now provided the docking results of this library with malarial enoyl reductase (PfENR). Here is what the top hit looks like:

So far we have been doing Ugi reactions usually with intensive NMR monitoring of each step. This has been very useful in debugging experimental conditions and reagent choice. Now that we have a better understanding of how to do it, generating many products quickly is more important than close monitoring.

We will take advantage of our observation that most of our Ugi products simply precipitate from solution over the course of a day. Instead of looking into additional purification techniques, we will make this an additional requirement for a compound to be considered a suitable lead. Any reactions that fail to precipitate within a day will be noted and discarded (see protocol). This information could surely be of use to others looking for suitable compound libraries. As for the testing phase of these potential anti-malarial agents, I have a few very promising leads now and I'll report shortly when I get confirmation of a collaborator.