Currently on our way...

1. Make a web site that links Raj, JCB, Phil ROsenthel and synaptic leap. (who they are and what they are capable of P Rosenthal -> assays for falcipain-2, paracites and mouse model)

2. Find the ultra structure of red blood cell/ malaria paracite (EM)

3. Get values (membrane potential/ pH etc ) write in a blog and link to literature. If not known think about how we can find out.

4. create Vcell model w/ and w/o malaria paracites the Red blood cell

What we need is a club.

Everybody has their own web page explaining things they are interested and good at.
But it matters less if it's not understandable in whole picture. We always want to have idea what does it mean to us.

So what we need is a webpage, that just scraps automatically to show what individual blog has been updated. Just like the facebook comments "Jason has updated his picture~!" or "Nan has just made friends with Xinyuan~!" Linking wouldn't do that. But just couple of scraps on main page, like newly updated news articles with little pictures. "Jessica Alba is now pregnant~ :("

It's more than just a link of allied scientists. It's more than group emailing. This can be called as WholePicture of the science where its flowing to. Not just presenting randomly to people that we want to do 'toxicity research' but where and how in a sense of 'Saving the World" linked to their own.

All begin from these letters

Gus wrote

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 presence 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 ofa transcellular concentration gradient (to minimize metabolism and toxicity 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. Alternatively, if the chemical structures cannot be revealed, I would just need the Chemaxon-calculated pKa of the functional groups of the molecule, the charges and microLogPs ofthe different ionized, and the micrologP of the neutral species.Once we give you the 1CellPK calculations, we can sit down together and figure out the best way to combine docking predictions with1cellpK predictions.


Rajarshi Guha wrote

I hope things are going well (probably hectic as well, at this time of the year). I had been exchanging some emails with Gus Rosania of the University of Michigan regarding working with the CombiUgi structures. I've included his email below.The gist of it is that he can calculate lysosomal concentrations of the drug in different environments (parasite, human cell etc) thus allowing us to rank the Ugi products on the basis of permeability,accumulation etc.This will provide another ranking in addition to the docking - it would be interesting to see how the current docking based rankings change when combined with these predictions - and hopefully be a better prioritization for compound selection.


And then Jean-Claude wrote

Thanks very much for getting me in touch with Gus!This looks like a very useful addition to the project.Gus, in terms of what can or cannot be revealed, we operate under Open Notebook Science conditions. That means that all aspects of the project,including raw data files, are made public in as close to real time as possible. The challenge with finding collaborators for our project is generally that scientists are not comfortable working in this way. If you are ok with that then I would start by asking permission to cite parts of your email on the Useful Chem blog: http://usefulchem.blogspot.com/

In terms of getting started, the most obvious place is to run your algorithm with library 3 (about 71K compounds)http://usefulchem.wikispaces.com/UClib003

Rajarshi used Lib03 to generate lists of compounds to make based on docking with falcipain-2:http://usefulchem.wikispaces.com/D-EXP014

For a list of all recent docking runs done see:https://web.mail.umich.edu/horde/services/go.php?url=http%3A%2F%2Fusefulchem.wikispaces.com%2FcombiugiWe have recently made a few of the compounds from D-EXP014 and have shipped them for testing against Falcipain-2https://web.mail.umich.edu/horde/services/go.php?url=http%3A%2F%2Fusefulchem.blogspot.com%2F2007%2F12%2Ffirst-falcipain-2-targets-shipped.htmlThis would be an excellent contribution to our drug development efforts and if you want to discuss further let me know a time we could talk.I'm also copying Dan Zaharevitz, who should be interested in your work.We've been working with him to synthesize anti-tumor compounds.

Drug Discovery Project

look for inhibitors of falcipain-2 to treat malaria.

Using Virtual Cell linking to
Transport, docking, distribution (Volume of distribution with the lipids. we need the lipid fraction in different compartments), metabolized and elimination(degradation) as in terms of ADME in pharmacokinetics.

Create on Synaptic Leap page under current projects.
ADME



cell pk = side by side Nan's (validation prediction) and Xinyuan's project(general modeling, simulation)
under 1 level, drug screening
under 2 level, antimalarial specific
under 3 level, falcipain-2
under 4 level, ADME, specific experiment links (JC compound, R docking, J subcell localization)

New use of WWW, the science outreach

Now the new era begins. Facebook and Second Life