Wednesday, August 08, 2007

Falcipain Collaboration

Thanks to Barry Bunin of Collaborative Drug Discovery, we now have a collaborator who will run assays on the compounds from our CombiUgi project. We'll be using our account on CDD to manage the activity results.

Phil Rosenthal from UCSF has agreed to run assays on the inhibition of falcipain-2, an enzyme used by the malaria parasite to digest hemoglobin. As described in UCSF magazine, the Rosenthal group discovered the enzyme and have developed an assay.

That means we'll have to do docking of our 500K library on falcipain-2. The PDB file is available here. Rajarshi and Tsu-Soo, are you up for another round?

Here is an email from Phil to clarify some more details:
We have been involved with docking studies before. Of course, Tack Kuntz at UCSF is a Dock pioneer. In general, Dock studies have identified some low uM inhibitors of falcipains, but it has been hard to move beyond this. However, these studies were based on models of FP structures, based on other papain-family enzyme structures. Now we have structures determined for the two key targets, falcipain-2 (the link that you sent) and falcipain-3 (not yet published, I am not sure if coordinates are yet available). These structures are from a structure group at UCSF. The key question is whether you will be offering a new approach compared to that used previously. It appears that the answer is yes, as you will have access to solved structures, and also to new chemistry methods. From our part, we’ll be happy to do the small number of screens that you envision. 5-10 compounds is quite trivial.

I mention to all collaborators that we have many collaborations with chemists interested in protease inhibitors as antimalarial drugs. Our major collaboration is with a group at GSK, and this project is well advanced using a traditional big pharma approach. We have academic collaborations with chemists in the US, Germany, Portugal, Venezuela, Cameroon, India, and South Africa (not only regarding protease inhibitors). I make it a point to be very open regarding the different collaborations but, of course, to respect each group’s confidentiality concerning results.

For a small set of compounds, we can do screening at any time. For larger projects, we can talk about the path forward. I’ll be in touch, and please let me know any time when you have compounds that you would like to screen or if you have any questions


At 10:59 PM, Blogger Rajarshi said...

Not a problem to set of more docking runs, though I might not get to it before the end of this month, after I get back from the ACS

But looking at the PDB structure seems to indicate that it's a protein-protein interaction. As a result the binding site seems to be very broad and shallow, which could be problematic. It's definitely interesting, since this'll be the first time I'm doing a PPI

The paper notes 3 catalytic residues, so I assume that that would be the focus of a docking protocol.

But I can certainly set of the runs

At 7:43 PM, Blogger Jean-Claude Bradley said...

Thanks Rajarshi!
I've started the thread on the mailing list with your comment.

At 8:14 PM, Anonymous Anonymous said...

I've just search about malaria and i found this blog. and i really like your blog.

At 10:00 AM, Blogger Unknown said...

I read the comments made on this blog and also was happy reading about the falcipain-2. I am just started my work on docking studies and i hope this blog will be helpful for me.

At 10:51 PM, Anonymous Sebastian said...

Hi Guys,

I'm a PhD student at Griffith University, Australia with the Eskitis Institute for Cell and Molecular Therapies and I'm doing my PhD thesis on antimalarial compounds and stumbled across your site. I'd love to get involved in the collaborative project but I have some questions regarding the open-ness / copyleft of this project, but couldn't find a contact link for any of the collaborators.

If anyone could email me at sebp @ tpg (dot) com (dot) au I would like to discuss these matters and if all is well, get on board.



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