CombiUgi virtual library generation via Google Spreadsheet

Andrew Lang has just created a service that lets anyone create a virtual library of Ugi products by entering the SMILES of the starting materials in a Google Spreadsheet.

First copy this template sheet (you must use File -> create a copy - copying and pasting cells will not work). Then publish the Google Spreadsheet under the Share tab.


Next add the key of your new Spreadsheet (as it appears in the URL) to a URL of this form:
http://showme.physics.drexel.edu/onsc/combiugi/combiugi.php?key=tR6lhYF_iqGdmceaAg-WRLg

The resulting page, which could take a long time to load for large libraries, can then be saved as a CSV file. On Firefox this is done by selecting Save As Text File.

If you put a CSV extension in the name you can then open the file directly in Excel:


All the results are in SMILES format and using all the tricks of Excel can be sorted or filtered even by reactant. One could also copy and paste to another Google Spreadsheet to manipulate the dataset.

This service replaces the one Rajarshi Guha had set up a while back at Indiana University. A key difference with this service is that it requires SMILES to be constructed as shown in the template sheet:

• N to the left for amines
• C(=O)O to the right for carboxylic acids
• O=C to the left for aldehydes
• [C-]#[N+] to the left for isocyanides

This requires a little knowledge of SMILES, especially for aromatic rings. I left a few examples with polysubstituted aromatics to show how this is done.

CombiUgi Update: the Master Table

It has been a while since my last update on the CombiUgi project. Those who have been following the UsefulChem wiki and mailing list will be aware of all the experiments and discussions but it helps to take a look at the big picture periodically.

My last post described our new focus on trying to make falcipain-2 inhibitors and Rajarshi was kind enough to do some docking runs for us. To keep costs low, we started using a library of Ugi products that we can make just from starting materials that we have in abundance (at least 5 g) in our lab.

Four undergraduate students have joined the group in the past few weeks and have been trained to perform the Ugi reaction in 1 dram vials. We initially started doing these in 1.5 ml Eppendorf tubes but they didn't seal perfectly with methanol and leaked during vortexing.

We are currently focusing on Ugi products which precipitate within a few days from the reaction mixture. We were very fortunate in that our first Ugi products crystallized from methanol. It turns out that not all Ugi products behave that way but we are hoping that enough will from the first few hundred falcipain-2 hits to have a handful of compounds to test.

Those reactions that generate pure products as precipitates are tremendously easier to run and scale up compared to requiring a chromatography purification step. If we can provide a list of Ugi products that can be easily prepared this way, I think that would be useful for other researchers with other applications in mind. Maybe we will identify patterns in different solvents that will enable us to understand (or at least empirically predict) how to induce precipitation for a given Ugi product. This kind of practical laboratory advice would add to the knowledge base of information on the Ugi reaction provided in a recent Nature Protocol report by Stefano Marcaccini and Tomás Torroba. (unfortunately not Open Access)

To keep track of all of this, results are pooled in a GoogleDoc Master Table on the CombiUgi page. Look on the experiment number to locate the experimental details from the experiment list page.

CombiUgi on MyExperiment

I've been lurking for a while on the MyExperiment mailing list and noticed that they just opened beta testing. I still don't know exactly how it can useful to help us do science beyond what we are doing but there's just one way to find out.

Of all of our activities I think that the CombiUgi project fits the workflow concept described by MyExperiment. It involves heavy systematic processing of information from the generation of the libraries to the docking evaluation then synthesis and testing.

Since Rajarshi Guha built the CombiUgi webservice to generate the virtual libraries I think we really need his input to see if this can make things easier.

I've created a project called CombiUgi but no workflows yet. You'll probably need to create an account on the beta site to view it.

CombiUgi: Time for Synthesis

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.