Hi Everybody,

You all found this news quickly! I was waiting until the press release was posted on the TSRI homepage before commenting here. Well, now it's ready at:

http://www.scripps.edu/newsandviews/i_20100208/hiv.html
There's a nice image at the above link that shows exactly where these two new "allosteric fragments" bind to HIV protease (i.e., look at the little green and cyan molecules). Since this is an experimental paper on crystallographic results (i.e., not a paper about computational docking results), further confirmation is not really needed. What we are focusing on now is extending these results, in order to try to turn these tiny, weakly-binding fragments into much larger, more complex, actual protease inhibitors.

You can also find a short news story about this paper at:
http://www.kpbs.org/news/2010/feb/04/discovery-may-lead-new-class-aids-drugs/


These links describe our new HIV protease paper, which will be the cover of the March, 2010, issue of "Chemical Biology & Drug Design."

Our new HIV protease paper describes the "X-ray crystallographic structures" that were produced by our innovative new strategy for fragment-based crystallographic screening. Thus, this paper describes the generation of the structures that we have been using as docking targets for virtual screens performed on FightAIDS@Home (but it does not present any of the docking results, which are not ready yet). Since I was part of this research, I was able to get permission from Assoc. Prof. C. David Stout at TSRI to use these new fragment-bound crystal structures of HIV protease as targets on FightAIDS@Home, long before this paper was approved for publication in a peer-reviewed journal.

We have been screening compounds against these new fragment-induced crystal structures since 03/03/2009 (see FAAH Experiments 25, 26, 27, 28, 30, and 31). We have been trying to find new allosteric fragments that bind to these two allosteric sites (see the images on pages 1, 4, and 6 of volume 8 of the FAAH Newsletter). In addition, we have been searching for new fragments that bind near these sites, so that we can try to attach them to the two fragments described in this paper (and, thus, try to make a larger, more potent allosteric compound). But let me be very clear--this protease paper does NOT present any new computational data from the WCG. This paper is all about experimental results that laid the foundation for previous, current, and future FAAH calculations.

This paper acknowledges FightAIDS@Home and the World Community Grid, since the WCG provides massive resources that enable, inspire, and motivate the entire multi-target, multi-lab, multi-year HIV collaboration. Having the WCG's resources helped Prof. Art Olson get funding from the NIH for a "program project grant" focused on drug-resistant HIV. This multi-lab program project grant provided the funding that allowed the crystallographic research described in this new paper to occur. This program project grant is also the reason why Assoc. Prof. C. David Stout and I started collaborating.

The HIV protease research described in this new paper was done to support and to extend the scope of the virtual screens we perform on the WCG. Because of these new fragment-bound crystal structures, we now know which particular conformations of HIV protease we should use as docking targets in these virtual screens. And we have been using these new fragment-induced crystal structures as docking targets on FightAIDS@Home for almost a year. Thus, although no WCG-generated data is presented in this paper, this paper describes new crystal structures of HIV protease that have allowed us to perform new types of virtual screens that should (hopefully) be much more fruitful, novel, and significant than our previous experiments on FightAIDS@Home.

Thank you all very much for your help and for your interest,
Alex L. Perryman, Ph.D.


PS--the crystallographic results described in this paper are the reason why we can now call these two surface regions of HIV protease actual "allosteric sites." We used to have to call them "putative allosteric sites" or "potential allosteric sites," but this paper presents the experimental proof that these two specific regions of HIV protease are in fact allosteric binding sites.

Thanks!

OUTSTANDING News!!!

Bump

Dear esoteric17,

I do read that thread every now and then, but it's too large of a thread for me to respond to the posts frequently.

I just read the press release about their new filters. Thank you very much for sharing that link with me! I'll study their research paper on this new approach very soon. It might be very helpful for several of my projects, including those on FAAH.

Cheers,
Dr. Alex Perryman