Speaker
Mr
Nicolas Jacq
(CNRS/IN2P3)
Description
Advance in combinatorial chemistry has paved the way for synthesizing large numbers
of diverse chemical compounds. Thus there are millions of chemical compounds
available in the laboratories, but it is nearly impossible and very expensive to
screen such a high number of compounds in the experimental laboratories by high
throughput screening (HTS). Besides the high costs, the hit rate in HTS is quite
low, about 10 to 100 per 100,000 compounds when screened on targets such as
enzymes. An alternative is high throughput virtual screening by molecular docking,
a technique which can screen millions of compounds rapidly, reliably and cost
effectively. Screening millions of chemical compounds in silico is a complex
process. Screening each compound, depending on structural complexity, can take from
a few minutes to hours on a standard PC, which means screening all compounds in a
single database can take years. Computation time can be reduced very significantly
with a large grid gathering thousands of computers.
WISDOM (World-wide In Silico Docking On Malaria) is an European initiative to
enable the in silico drug discovery pipeline on a grid infrastructure. Initiated
and implemented by Fraunhofer Institute for Algorithms and Scientific Computing
(SCAI) in Germany and the Corpuscular Physics Laboratory (CNRS/IN2P3) of Clermont-
Ferrand in France, WISDOM has deployed a large scale docking experiment on the EGEE
infrastructure. Three goals motivated this first experiment. The biological goal
was to propose new inhibitors for a family of proteins produced by Plasmodium
falciparum. The biomedical informatics goal was the deployment of in silico virtual
docking on a grid infrastructure. The grid goal is the deployment of a CPU
consuming application generating large data flows to test the grid operation and
services. Relevant information can be found on http://wisdom.eu-egee.fr and
http://public.eu-egee.org/files/battles-malaria-grid-wisdom.pdf.
With the help of the grid, large scale in silico experimentation is possible. Large
resources are needed in order to test in a transparent way a family of targets, a
large enough amount of possible drug candidates and different virtual screening
tools with different parameter / scoring settings. The grid added value lies not
only in the computing resources made available, but also already in the permanent
storage of the data with a transparent and secure access. Reliable Workload Manager
System, Information Service and Data Management Services are absolutely necessary
for a large scale process. Accounting, security and license management services are
also essential to impact the pharmaceutical community. In a close future, we expect
improved data management middleware services to allow automatic update of compound
database and the design of a grid knowledge space where biologists can analyze
output data.
Finally key issues to promote the grid in the pharmaceutical community include cost
and time reduction in a drug discovery development, security and data protection,
fault tolerant and robust services and infrastructure, and transparent and easy use
of the interfaces.
The first biomedical data challenge ran on the EGEE grid production service from 11
July 2005 until 19 August 2005. The challenge saw over 46 million docked ligands,
the equivalent of 80 years on a single PC, in about 6 weeks. Usually in silico
docking is carried out on classical computer clusters resulting in around 100,000
docked ligands. This type of scientific challenge would not be possible without the
grid infrastructure - 1700 computers were simultaneously used in 15 countries
around the world. The WISDOM data challenge demonstrated how grid computing can
help drug discovery research by speeding up the whole process and reduce the cost
to develop new drugs to treat diseases such as malaria. The sheer amount of data
generated indicates the potential benefits of grid computing for drug discovery and
indeed, other life science applications. Commercial software with a server license
was successfully deployed on more than 1000 machines in the same time.
First docking results show that 10% of the compounds of the database studied may be
hits. Top scoring compounds possess basic chemical groups like thiourea, guanidino,
amino-acrolein core structure. Identified compounds are non peptidic and low
molecular weight compounds.
Future plans for the WISDOM initiative is first to process the hits again with
molecular dynamics simulations. A WISDOM demonstration will be conceived at the aim
to show the submission of docking jobs on the grid at a large scale. A second data
challenge planned for the fall of 2006 is also under preparation to improve the
quality of service and the quality of usage of the data challenge process on gLite.
Primary author
Mr
Nicolas Jacq
(CNRS/IN2P3)
Co-authors
Dr
Astrid Maaß
(Fraunhofer SCAI)
Mrs
Florence Jacq
(CNRS/IN2P3)
Dr
Horst Schwichtenberg
(Fraunhofer SCAI)
Mr
Jean Salzemann
(CNRS/IN2P3)
Mr
Kasam Vinod-Kusam
(Fraunhofer SCAI)
Mr
Mahendrakar Sridhar
(Fraunhofer SCAI)
Dr
Marc Zimmermann
(Fraunhofer SCAI)
Dr
Martin Hofmann
(Fraunhofer SCAI)
Mr
Matthieu Reichstadt
(CNRS/IN2P3)
Dr
Vincent Breton
(CNRS/IN2P3)
Mr
Yannick Legré
(CNRS/IN2P3)
