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