Plasmepsins (PMs) are essential proteases of the plasmodia parasites and are 
therefore promising targets for developing drugs against malaria. We have 
discovered six inhibitors of PM II by high-throughput fragment-based docking of 
a diversity set of approximately 40,000 molecules, and consensus scoring with 
force field energy functions. Using the common scaffold of the three most active 
inhibitors (IC(50)=2-5 microM), another seven inhibitors were identified by 
substructure search. Furthermore, these 13 inhibitors belong to at least three 
different classes of compounds. The in silico approach was very effective since 
a total of 13 active compounds were discovered by testing only 59 molecules in 
an enzymatic assay. This hit rate is about one to two orders of magnitude higher 
than those reported for medium- and high-throughput screening techniques in 
vitro. Interestingly, one of the inhibitors identified by docking was 
halofantrine, an antimalarial drug of unknown mechanism. Explicit water 
molecular dynamics simulations were used to discriminate between two putative 
binding modes of halofantrine in PM II.