Plasmepsins are aspartic proteases involved in the degradation of the host cell 
hemoglobin that is used as a food source by the malaria parasite. Plasmepsins 
are highly promising as drug targets, especially when combined with the 
inhibition of falcipains that are also involved in hemoglobin catabolism. In 
this review, we discuss the mechanism of plasmepsins I-IV in view of the 
interest in transition state mimetics as potential compounds for lead 
development. Inhibitor development against plasmepsin II as well as relevant 
crystal structures are summarized in order to give an overview of the field. 
Application of computational techniques, especially binding affinity prediction 
by the linear interaction energy method, in the development of malarial 
plasmepsin inhibitors has been highly successful and is discussed in detail. 
Homology modeling and molecular docking have been useful in the current 
inhibitor design project, and the combination of such methods with binding free 
energy calculations is analyzed.