The CommunityTSC project uses Sengent’s CommunityOS™ Grid computing
framework and its D2OL™ software and the idle time on your personal computer to help make
drugs to treat patients with TSC. It is safe and does not interfere with any other operation of your
computer.
CommunityOS™ lets us tie 1000's of computers into a single machine able to rival (or beat
with more volunteers) the worlds largest super computers. D2OL™ is the software program that
is downloaded to your computer and used to evaluate drug candidates for Tuberous Sclerosis. Again,
no knowledge needed, and if you close the window it runs invisible behind the scenes.
The Rothberg Institute is funding some of the best researchers
at Harvard, Yale, and the Fox chase cancer center to find new
targets for intervention in the treatment of TSC. Those targets
are fed into drug development programs right at the ICCB at Harvard,
as well at the Rothberg Institute.
D2OL™ searches millions of candidate compounds
(about 2 million of these compounds are available to purchase
from chemical suppliers around the world) for potential drugs
that fit into the targets we discover, like fitting a key to
a lock. As a user, no intervention is required and the software
will test candidates as long as it is running. You do not need
to be connected to the internet for it to work.
The science of using computers to screen for potential drugs from large collections of candidates against targets that have had
their structures determined is known as "Virtual Library Screening".
Since D2OL™ is actually a computing and graphical framework that allows us to use the best software as
it is created anywhere in the world to do drug design, we will be both improving the Virtual Screening programs as well as adding
programs to do atom-by-atom "de novo" drug design.
In addition to taking existing small molecule compounds found in chemical libraries and fitting them to targets that we discover
are related to TSC we plan on taking a parallel approach based on making new drugs atom-by-atom to fit into the targets we discover.
While this approach seems like science fiction, recent advances by a new member or our scientific advisory board suggest that
this approach may have significant advantages of any approaches taken to date. So stay tuned....
Scientists sponsored by the TS Alliance Rothberg Courage Award representing
institutions like Yale, Harvard and Fox Chase Cancer Research Center have layed out the molecule pathway
involved with TSC. It is through the understanding of this pathway that specific drug targets are being
elucidated. To date six of the genes and their corresponding proteins from the TSC pathway have had their
3D structure discovered by x-ray crystallography.
Recent work elucidating the TSC pathway by Rothberg Courage Award sponsored
scientists:
mTOR is the mammalian target of rapamycin
FRAP is the fragment (protein) that binds rapamycin
Targets
Insights gained from the recent "Prospects in Tuberous Sclerosis" conference held
in Chantilly, Virginia, prompted us to add an additional two targets to the repertoire of the Virtual
Screening project targets. In particular the mammalian target of Rapamycin (mTOR) has been fingered as a
potential therapeutic targets. The fragment of mTOR which binds rapamycin (mTOR, a.k.a. FRAP) has a published
crystal structure and will be the third target for virtual library screening. The eukaryotic initiation
factor 4E (EIF4E) has been identified as another potential therapeutic target. This protein is located further
along the signaling cascade being turned on by mTOR. Thus both mTOR & EIF4E expression and function are affected
by the loss of function in TSC1 or TSC2. Akt has been shown to phosphorylate Tuberin (protein product of the TSC2 gene)
which inhibits the formation of the Tuberin/Harmatin complex. This expands the total number of proteins undergoing
virtual library screening to five. You can read more about all six targets in the respective publications below:
Potential drugs that come from this project will first be tested at both The Rothberg Institute as
well as at the institutes of our sponsored labs at Harvard, Yale, Fox Chase and other institutions that receive TS
Alliance Rothberg Courage Awards. In addition, our scientific advisory panel, consisting of leading experts in human
genetic, complex diseases, cell biology, chemistry and medicine will help insure both the selection of the correct targets,
improvements to the methods used to do the screening on your home computer, as well as, and most importantly rapid follow
up, testing and eventual development of any potential drugs that emerge.
We are far from having the best targets yet for TSC, as well as the best targets for cancer
which TSC may prove to be the Rosetta Stone for, and we are far away from perfecting the computer programs (the docking
and virtual drug screening we talk about), but through these efforts, and your contribution we will be able to close the
gap.
(PDF) 05/2002
