Tuesday, December 18, 2007

Subcellular Drug Transport UsefulChem Collaborator

Rajarshi Guha has yet again made a key contribution to our UsefulChem project by connecting us with Gus Rosania at the University of Michigan. Gus is interested in a fully open collaboration to help us further prioritize our drug targets based on predicted subcellular drug transport:

It is the first time I hear about Open Notebook Science, but it sounds like a fantastic idea!

My research group studies the subcellular transport of small molecules. We are interested in combining cellular distribution of small molecules together with systems biology, to analyze the pharmacological activity of small molecules in a cellular (and organismic) context. For more information about our subcellular transport lab, you can visit us at http://www-personal.umich.edu/~grosania/

Indeed, one of our objectives is to make all our cellular pharmacokinetic models open source, so that they can be modified, evolved and used for educational purposes and as virtual drug discovery tools, throughout the world. We are porting all our models to Virtual Cell (http://vcell.org/), where they are in a form that can be freely accessed and distributed on-line, though a simple graphical user interface Plus, Virtual Cell sponsors courses in computational modeling and systems biology as well as conferences, so it is more than just a modeling tool. As we work on this, we would like to explain what we are doing step-by-step, for everyone else to follow.

Gus provides more details about what his group can do:

We can readily calculate on-target lysosomal drug concentrations, vs. off-target mitochondrial or cytosolic drug concentrations. Question: are the inhibitors small "drug-like" molecules, peptides(or some other awful thing)? If they are small drug-like molecules, then we are good.

With 1cellPK we can identify the inhibitors that would lead to greatest accumulation in lysosomes of a cell surrounded by a homogeneous extracellular drug concentration (the parasite) while minimizing the accumulation in lysosomes of an off-target cell (ie the intestinal epithelial cell mediating absorption in the pesence of a transcellular concentration gradient). With 1CellPk we should also able to select those molecules with the highest transcellular permeability (for oral administration) while at the same time accumulating minimally in the cytosol of cells in the presence of a transcellular concentration gradient (to minimize metabolism andtoxicity in intestinal epithelial cells and hepatocytes, while maximizing intestinal absorption and systemic bioavailability).

There are several ways we can actually execute the collaboration. At the most basic level, if you give me the compounds' chemical structures, I can run them through 1cellPK (in Virtual Cell), and estimate their permeability, intracellular accumulations and distribution in the parasite, as well as in non-target intestinal epithelial cells. Once we give you the 1CellPK calculations, we can sit down together and figure out the best way to combine docking predictions with 1cellpK predictions.

Our falcipain-2 project is an obvious place to start.

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At 11:05 AM, Blogger Gus Rosania said...

Thanks for posting my email. Actually, I am totally new to blogging, but this project has got me really excited. I went ahead and made a project page at The Synaptic Leap. Now I am looking how to organize the "lab notebooks" of my students. Looks like you are primarily working through "The Wiki" and "RSS feeding" pertinent information to other blogs...am I right? Can you give me some general pointers (and warnings, if necessary) in terms of organizing my students' blogs/notebooks? Your advice to get my lab into Open Notebook Science mode is greatly appreciated.

At 3:38 PM, Blogger Jean-Claude Bradley said...

Gus - I am also excited by the prospect of collaborating with your group!
For an explanation of how Open Notebook Science and UsefulChem evolved and works probably the best source is a recent talk I gave at Swarthmore.
If you are going to be prioritizing lists of SMILES with your algorigthms, the format of your experiments will probably look like Rajarshi's runs. We create a "docking experiment" page (D-EXP) for each run. You can see the list here. The easiest way to collaborate would be to create a wiki page for your experiment and link back to our libraries. That way you can edit whatever you want easily. Just hit "Join this Space" when you are on the UsefulChem wiki and I'll give you an account. I can walk you through any of this over the phone if you like.

Other options include our mailing list. You'll see several threads involving Rajarshi's docking work. That seems to work well for debugging stuff.

You may wish to post to the UsefulChem blog or start your own blog. Either way I can help. The key thing is to get started with something simple and realistic. If you can start with prioritizing lib03 things will fall into place.

At 7:04 PM, Blogger Gus Rosania said...


I just finished the beginning of my own lab's wikispace. You can visit us at

Thank you for including me as a member in Usefulchem. I would be happy to include you as a 1cellpk member, as well. Just send me a request.

Again, thank you for introducing us to the Open Notebook Science concept. --Gus Rosania


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