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January
30, 2009
In
response to the following question posted on the World Community Grid
forum:
Q:
“Obviously, we know the project is back up and running again (it appears
to still being 'throttled back' though), and thus, I was wondering, have all
the scientists/staff managed to get their lives (and labs) back in full
working order yet?”
A:
Good
question! We have asked the IBM to rein in this project a little; hence, we
are not receiving equivalent processing time as other projects. There were
several factors for this decision. (1) Although we are up and running, we
are not yet fully recovered at UTMB. The campus and community (and hence our
staff) continue to rebuild, but this will take time and money (and only one
of those items is assured). (2) We are still evaluating our new disk storage
arrangement. Until we have more experience with its operation, we decided to
temporarily reduce the data flow we receive from the grid (since each target
generates ~0.5 TByte of information, we are seeing how well we handle 1
TByte/month of incoming data before again ramping up this project). (3) We
have ~4 more antiviral targets (mainly HCV) and 6 Leishmania targets to
examine in Phase 1. However, we are behind in analyzing and testing Phase 1
results received for the dengue and West Nile protease targets. Thus, we are
playing catch-up with the results we have received from your computers.
Delays in analyzing Phase 1 results are due to Hurricane Ike and from
shifting the efforts of our computational chemists more towards the Phase 2
calculations. Delays in "wet bench" testing of Phase 1 results are
due to Hurricane Ike damage and the time-consuming nature of these
experiments.
So,
at this point we are hard-pressed to keep up with the data generated by the
grid (too many ever-increasing powerful computers out there). However, I
suspect that the grid will need to grow even more to return our Phase 2
calculations as fast as we would like ... we will see shortly ...
January 18, 2009 update
On
January 18, 2009, our World Community Grid project “Discovering Dengue
Drugs-Together” resumed sending out workunits to grid clients around the
world. This project has been off-line since September 13, 2008, when
Hurricane Ike devastated Galveston, Texas and our university. We thank World
Community Grid members for their support and patience as we rebuild our
damaged infrastructure and community. Much is left to do to fully recover,
but at least this project is restored.
Our
initial projections as to how long it would take to restart operations were
clearly overly optimistic. Recounting the myriad of large and mundane
problems that were faced to get back on-line is a little mind-numbing at
this point. However, in brief, most personnel on this project lost their
homes and possessions, and needed to focus on family recovery. Our main
computer cluster sustained damage and remains unstable (contrary to initial
assessments). Disk storage components were lost to flood waters and have
taken time to replace. Institutional support for this project was reduced as
the University of Texas Medical Branch cut ~25% of its staff.
On
the positive side, this project is now running better than ever before. We
have moved our main computational tasks (those required to prepare workunits
for World Community Grid and analyze results returned from the grid) to the
supercomputers housed at the Texas Advanced Computer Center (TACC;
www.tacc.utexas.edu) in Austin, Texas. Our pre- and post-processing
calculations execute 10x faster in this environment compared to our in-house
30-node computer cluster. Thus, we have established a nice synergy between
one of the world’s most powerful supercomputers and the world’s largest
computer grid. Our storage capabilities have increased in (1) size with the
local addition of IBM’s 12 TByte DS3200 disk subsystem and (2) robustness
with redundant storage occurring at TACC and locally. Programs required to
accurately calculate free energy of binding (Phase 2 of this project) have
been tested and optimized at TACC, and are being ported to the grid. Thus,
the computational side of this project is more powerful and dynamic than
before Hurricane Ike.
The
current tasks before us are clear. (1) We will resume pre-clinical
characterization of potential dengue, West Nile, and hepatitis C virus
protease inhibitors predicted by our Phase 1 calculations. Several Phase 1
compounds have shown promising in vitro activity. (2) Launch Phase 2 free
energy of binding calculations to reduce the large false-positive rates
associated with virtual screening. Finally, our newly established
synergistic World Community Grid/TACC environment will help us tackle
additional global health projects – with IBM’s support we are about to
launch a collaborative drug discovery effort with researchers in South
America to target the Leishmania parasite.
As
stated before, we greatly
appreciate the computer time that has been unselfishly provided by the
members of the World Community Grid. Your interest and support has made this
grid one of the most powerful computing resources on the planet!
December
17, 2008
Hello
from UTMB! No, we are not inactive. Yes, we are bringing this project back
online. Yes, it is taking us longer than expected since we continually run
into unexpected personnel and infrastructure surprises. But, behind the
scenes, we are working hard and are committed to bringing this project back
online. The coding and testing of Phase 2 (free energy calculations) of this
project is occurring even as Phase 1 sits apparently silent.
Our
main LINUX cluster used for pre/post processing of workunits and storage of
the vast amount of information generated by your crunching computers was
offline. Now, only our 12 TB IBM DS3200 storage system is offline. We are
reinstalling 3rd party interface boards and drivers to bring this system up
(if this fails, we will move this storage system to another cluster, and
work from there). Surprising, as it may seem, this is taking time.
Thank
you for your continued patience.
Best
wishes to all for this Holiday Season from the DDD-T group at UTMB.
September
30, 2008
A
quick update on our project, which was greatly impacted by Hurricane Ike
when it tore through the Houston-Galveston area ~16 days ago. Houston, the
4th largest city in the US, is recovering quickly from this massive storm.
Power is largely restored to most residents (including my own home). It was
very strange and quiet to be without electricity and internet for many days.
Unfortunately,
Galveston and the University of Texas Medical Branch (where this project
originates) were very hard hit by the hurricane's storm surge. Fortunately,
prudent preparations kept most residents and staff safe. However, it will
take Galveston many months (to years) to completely rebuild and recover from
the storm's destruction. Galveston remains largely without power, and water
is problematic in many places. Yet, even without power, cleanup and
rebuilding operations are in full swing.
Our
current priority remains getting our students and researchers dug out, dried
off, and moved into new apartments (in my lab alone, over 60% of the
students/post-docs lost their apartments and all possessions due to flooding
and wind damage). Once our staff and their families are secured and
resettled, the campus repaired, and our labs reopened, our DDDT project will
return to full production mode. We are working hard to have this
accomplished within the next 2 weeks. Until then, thank you for your help
and keep your computers dry and crunching fast.
Pre-Ike,
we tested the first set of dengue and West Nile inhibitors predicted by our
Phase 1 calculations (0202 and 0203 workunits). We were delighted to find
several compounds that were highly effective protease inhibitors. Once our
labs reopen, we will test the antiviral activity of these compounds in cell
culture. We are very encouraged by the preliminary Phase 1 results, and look
forward to starting our Phase 2 calculations to improve the success rate of
our antiviral drug discovery calculations.
June 3, 2008 update
·
Our Discovering Dengue Drugs – Together project has currently
benefited from >6,000 years of computer processing time on World Community
Grid. We are extremely grateful and indebted to those individuals who have
unselfishly volunteered their computers to help us search for cures to
dengue, West Nile, and Hepatitis C diseases.
·
Trypsin protease (Protein Data Bank entry 1EB2) has been
screened against our 2.2 million member ligand library to provide a negative
control for inhibitor discovery (termed workgroup 0401).
·
Hepatitis C virus protease was used as a target to screen a
combined drug and lead-like library containing 2.2 million compounds. These
calculations (termed workgroup 0501) were completed in ~ 2 months.
·
A second optimization of the Autodock program and its
parameters was completed in late April 2008. This included modifying the
code to enable multiple ligands to be combined into a single workunit for
delivery to end-user computers. Although this increased the execution time
for each workunit, this has decreased network traffic on the World Community
Grid servers and enabled more ligands for the DiscoveringDengueDrugs-Together
project to be distributed. This has allowed our workflow to increase by ~2-
to 3-fold.
·
Recoding and porting the CHARM molecular dynamics program for
use on World Community Grid is underway. The CHARMM program will be the main
software for Phase 2 of this project. It will enable us to accurately
calculate free energies of binding for tens of thousands of the best fit
protease-ligand structures determined in the Phase 1 Autodock calculations.
These calculations are necessary to correct false-positive energy
predictions made by the Autodock scoring function.
·
A variant of the dengue virus NS3 protease was used as a
target to screen a combined drug and lead-like library containing 2.2
million compounds. These calculations (termed workgroup 0202) were completed
in <1 month.
·
A variant of the West Nile virus NS3 protease was used as a
target to screen a combined drug and lead-like library containing 2.2
million compounds. These calculations (termed workgroup 0302) were completed
in <1 month.
·
We are preparing to launch a new version of the Phase 1
Autodock software that contains error checking embedded within each workunit.
This will eliminate the use of duplicate (or triplicate) calculations to
validate each workunit. This improved code should allow us to reach our goal
of screening our ligand library against a single protein in less than 2
weeks.
·
The combined results from screening our ligand library against
the dengue virus NS3 protease and a dengue protease variant are being
analyzed in our laboratory to identify common hits (i.e., compounds
predicted to fit into the protease active site). These results will be
filtered to remove inhibitors predicted to bind trypsin, since broad
inhibitors may have adverse human effects. Compounds with promising
inhibition constants and specific dengue protease binding will be
synthesized and evaluated in cell culture and animal models.
·
The combined results from screening our ligand library against
West Nile and dengue proteases are being analyzed in our laboratory to
identify potential flavivirus protease inhibitors. These results will be
filtered to remove compounds predicted to bind trypsin, since broad-spectrum
protease inhibitors may have adverse human effects. Compounds with promising
inhibition constants and specific flavivirus protease binding will be
synthesized and evaluated in cell culture and animal models.
January 22, 2008 update
·
An initial optimization of docking parameters was completed in
early Fall, 2007. This allowed us to reduce computation time ~20-fold
without impacting the accuracy of pose predications.
·
Dengue virus NS3 protease (Protein Data Bank entry 2FOM) was
used as a target to screen a combined drug and lead-like library containing
2.2 million compounds. These calculations (termed workgroup 0201) were
completed in ~2 months. Grid resources for these calculations were limited
to <10% of World Community Grid to minimize file transfer bottlenecks
resulting from packing only a single ligand into each workunit.
·
Predicted inhibitors obtained from screening our ligand
library against dengue virus NS3 protease are being analyzed in our
laboratory using a protease inhibition assay. Compounds with promising
inhibition constants will be further evaluated in cell culture and animal
models.
·
West Nile virus NS3 protease (Protein Data Bank entry 2FP7)
was used as a target to screen a combined drug and lead-like library
containing 2.2 million compounds. These calculations (termed workgroup 0301)
were completed in ~2 months and ended in early January ‘08. Grid resources
for these calculations were also limited to <10% of World Community Grid to
minimize file transfer bottlenecks resulting from packing only a single
ligand into each workunit.
·
Predicted inhibitors obtained from screening our ligand
library against West Nile virus NS3 protease are being analyzed in our
laboratory using a protease inhibition assay. Compounds with promising
inhibition constants will be further evaluated in cell culture and animal
models.
·
Additional docking calculation optimizations are entering beta
testing. These optimizations will enable us to reach our goal of screening
our ligand library against a single protein in less than 2 weeks. This
involves packaging multiple ligands (~10) into a single workunit, thereby
minimizing file transfer bottlenecks. In addition, checksum error checking
will be embedded within each workunit, eliminating the use of redundant
calculations to validate each workunit.
·
Trypsin protease (Protein Data Bank entry 1EB2) is being
screened against our ligand library to provide a negative control for
inhibitor discovery (termed workgroup 0401).
·
Hepatitis C virus protease is being readied for computational
screening.
·
Our Discovering Dengue Drugs – Together project has currently
benefited from 3,626 years of computer processing time on World Community
Grid. We are grateful to those individuals who have unselfishly volunteered
their computers to help us find cures for dengue, West Nile, and Hepatitis C
diseases.
August 21, 2007 update
·
Phase 1 (Autodock) of this project was launched August 21,
2007.
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