The Fall 2008 ACS meeting ends

It is always nice for a major conference to happen on home turf. Last week the American Chemical Society held its fall meeting in Philadelphia.

I finally got to meet my Second Life collaborator Andrew Lang during our first talk on Monday August 18, 2008. We presented on what is now possible to do for chemistry in Second Life. There are now several easy to use tools for chemistry and molecular biology. For example, Andy has created a tool to display protein surfaces using a lightweight sculpted prim from a PDB file. Take a look at the slides from the presentation for a quick overview.


I gave another talk on Monday about Second Life and Social Media: Networking Goldmine or Time Sink? It was a nice opportunity for me to talk about major success stories (Bora Zivkovic, Beth Ritter-Guth and Deepak Singh) as well as specific examples from my own experience. Sandy Adam from Sigma-Aldrich and Andy Lang contributed their own stories at the end. The take home message was that if you treat these platforms as a means of participating with your scientific community you're likely to get out of it more than you put in.

On Wednesday I spoke about Open Notebook Science and the value of raw data in drug discovery. The timing was perfect, since I had just finished analyzing the correlation of our docking predictions with biological assays against falcipain-2 and Plasmodium falciparum. (data here)

Ugi Precipitation Predictions

Following a recent discussion about the Ugi Master Table, things got sorted out enough that Rajarshi has built a model to predict which of the top 100 molecules from his docking run against falcipain-2 (V2 receptor) are most likely to precipitate the Ugi product. He get 6 hits, 3 of which are part of the training set and 3 have not yet been attempted yet. The new ones are here:

Hit 87

Hit 83

Hit 72

As we get more information in the table, we can start formulating new hypotheses. One of the factors that I have suspected for a while is that the products that precipitated tended to come from less concentrated solutions. Now we are starting to get results from the same Ugi reactions at different concentrations, where this effect should be more obvious.

For example this compound precipitated from a 1 mmol scale reaction with 4 ml of methanol but remained in solution at a 0.25 mmol scale with 0.25 ml of methanol.

This seems counterintuitive because one would expect increasing the concentration should make it easier to precipitate. But I think those solutions are so concentrated that the reagents compete as role of solvent with methanol.

Rajarshi has not yet taken into account the role of concentration but we have discussed it and can more easily do so as we accumulate more results.

We Have Anti-Malarial Activity!

The results are in.

Jiri Gut from the Rosenthal group has run 2 of our Ugi products and they both show inhibition of falcipain-2 (EXP165) and Plasmodium falciparum (EXP166) in the micromolar range.

To put this in context the activities are roughly 2 orders of magnitude lower than the positive control used for the enzyme inhibition and chloroquine for the parasite.

But it is a start. And we have officially closed the Open Science Loop for the malaria project, meaning that we have openly documented the docking results from Rajarshi Guha (D-EXP014), our syntheses (EXP148 EXP150) and testing (EXP165 EXP166) in the Rosenthal group.

We can't tell much about the validity of Rajarshi's docking model from the results of two compounds but as more data come in the situation should become clearer.

However, Jiri did make this interesting observation:

The food vacuole abnormality, which is indicative of cysteine protease inhibition was not observed in the parasites, suggesting other mode of action.

First Falcipain-2 Targets Shipped

We've reached an important milestone on our CombiUgi project involving the synthesis of falcipain-2 inhibitors. In my last update I described how our focus was more on doing many reactions in parallel and only looking for Ugi products that precipitate in pure form within a few days.

It took little longer than I hoped. In order to do more reactions, we reduced our efforts towards monitoring. One of the assumptions that we made was to trust a bottle's label to accurately describe its contents. That turned out to be incorrect for one of our key aldehydes, as we eventually found out by systematically taking NMRs of the starting materials. Soon after ordering a new bottle of phenanthrene-9-carboxaldehyde we were treated to the growth of beautiful crystals (see EXP150 by Khalid and Emily):

This compound was ranked 155th out of 71,000 Ugi products for docking with falcipain-2 at potential receptor site V1 (see full description by Rajarshi Guha here).

This compound, along with another (EXP148) that crystallized similarly, have been shipped to the Rosenthal group at UCSF for testing against the malarial parasite and hopefully get some falcipain-2 inhibition assay results. That way we'll be able to investigate the validity of our docking model.

I'll be posting updates on this blog but the status of any shipped compounds will be maintained on the isolated compounds table.

If anyone would like to run their own assays please contact us. We would be happy to ship any of these compounds, as long as our collaborators are willing to work under Open Notebook conditions.

The beauty of screening for products that are purified by crystallization is that, if any of these prove to be useful for any application, it should be very simple and cheap to produce several kilograms. This can come in handy for end users with very limited resources.

Chemical Blogspace Tags

InChI=1/C15H10O/c16-10-12-9-11-5-1-2-6-13(11)15-8-4-3-7-14(12)15/h1-10H
Phenanthrene-9-carboxaldehyde

InChI=1/C5H9N/c1-5(2,3)6-4/h1-3H3
tert-butylisocyanide

InChI=1/C4H6O2/c1-2-3-4(5)6/h2-3H,1H3,(H,5,6)/f/h5H
Crotonic Acid