WISDOM: A Grid-Enabled Drug Discovery Initiative against Malaria - Grid Computing: Infrastructure, Service, and Applications - page 365

recombinant plasmepsin II activity without an inhibitor was used as a neg-
ative control and pepstatin A was used as a positive control. Pepstatin A
showed inhibition (subnanomolar) against the recombinant plasmepsin II
activity. Among 30 compounds selected for biological tests, 26 compounds
revealed subnanomolar IC 50 values, but four compounds had no inhibitory
activity. And three compounds showed similar or better inhibitory activity
compared to Pepstatin A. These results are extremely encouraging and
suggest that the overall approach used to select the candidates is sensible
for discovery of new plasmepsin inhibitors. The seven compounds are cur-
rently being evaluated for their antimalarial activities in vitro .

14.4 Second Data Challenge on Malaria

14.4.1 Introduction

With the success achieved by the i rst data challenge on both the compu-
tation and biological sides, several scientii c groups around the world
proposed targets implicated in malaria that led to the second assault on
malaria. The WISDOM-II project dealt with several targets, which were
both X-ray crystal structures and homology models. Targets from differ-
ent classes of proteins were also being tested: reductases such as malarial
dihydrofolate reductase (DHFR) and transferases such as glutathione
S-transferase (GST) as can be seen from Table 14.2 . The same procedure
described previously for the i rst data challenge was applied for target
preparation. We again had the privilege of being able to use the FlexX
software, thanks to the generous support of BioSolveIT.
DHFR and dihydropteroate synthase (DHPS) are two enzymes that
belong to the folate biosynthetic pathway. The antifolates are the most
exploited class of antimalarials, to which belong well-known molecules
like pyrimethamine and cycloguanil. To date, the most widely used anti-
folate is a combination of pyrimethamine, a DHFR inhibitor, and sulfa-
doxin, a DHPS inhibitor. Nevertheless, their synergic action that results in
enhanced activity is seriously compromised by drug resistance and hyper-
sensibilization. For example, drug resistance is due to point mutations of
various amino acids in the DHFR and DHPS ( P. falciparum and P. vivax )
active sites, and severely decreases drug efi cacy. Although most antima-
larial research has been conducted on P. falciparum DHFR, there is growing
interest in P. vivax DHFR, a less-studied target that is becoming increas-
ingly important because mixed falciparum and vivax infections are
increasing, and parasites have developed resistance to both. Therefore,
there remains a pressing need of new molecules apt to selectively bind
these targets. To date, six different malarial DHFR crystal structures are