WISDOM: A Grid-Enabled Drug Discovery Initiative against Malaria - Grid Computing: Infrastructure, Service, and Applications - page 371

The results rei ned with MD at the University of Modena for wild-type
P. falciparum DHFR showed that the identii cation of novel families of anti-
malarials whose structures are not related to classical antifolates is indeed
possible. For wild-type P. falciparum DHFR, the best 15,000 compounds
resulting from the docking screening (FlexX) have been rei ned with the
MD procedure, and the molecules have been rescored using MM-PBSA
and MM-GBSA. Hydrogen bond analyses of the 15,000 ligands interacting
at the active site revealed a signii cant enrichment of hydrogen bonds with
DHFR key residues Asp54, Ile14, and Ile164 (as well as their combinations)
in the i rst ranking positions. This i nding may validate the approach,
because interaction with these residues is known to be required for
biological activity.
In perspective, MD rei nement will also be performed on the results
obtained with the quadruple mutant DHFR structure and the results
generated with P. v iv a x DHFRs. Once the analyses are complete, a i nal
selection of potential inhibitors will be performed and the best candidates
will be tested in vitro at Mahidol University (Thailand) in Worachart
Sirawaraporn's laboratory. MD rei nement of the results obtained on GST
has been performed in collaboration with the University of Modena, and
the results of this rescoring step are presently under analysis.

14.5
The WISDOM initiative has demonstrated how the grid can signii cantly
change the approach to screening, which is a mandatory step on the road
to drug discovery. In the last couple of years, a number of targets have
been screened in silico using grid infrastructure resources. The molecules
that have been selected through this process have shown signii cant inhi-
bition activity in vitro and some of them are under a patenting process.
The grid added value has been clearly demonstrated by the remarkable
increase of the virtual screening throughput up to 100,000 docked com-
pounds per hour using 5000 computers on the EGEE grid.
Following this success, the WISDOM initiative, started from discussions
between Martin Hofmann and Vincent Breton at the PharmaGrid confer-
ence in Welwin City in July 2003, has turned into a collaboration that has
seven partners today:

Conclusion and Perspectives

• CNRS in Clermont-Ferrand (http://clrpcsv.in2p3.fr), with exper-

tise in grid technology and Web services for life sciences
SCAI Fraunhofer institute in Bonn, with expertise in biochemoin- •

formatics, and text-mining technology, and author of the FlexX
docking software