The development of efficient and selective antimalariais remains a challenge for 
the pharmaceutical industry. The aspartic proteases plasmepsins, whose 
inhibition leads to parasite death, are classified as targets for the design of 
potent drugs. Combinatorial synthesis is currently being used to generate 
inhibitor libraries for these enzymes, and together with computational 
methodologies have been demonstrated capable for the selection of lead 
compounds. The high structural flexibility of plasmepsins, revealed by their 
X-ray structures and molecular dynamics simulations, made even more complicated 
the prediction of putative binding modes, and therefore, the use of common 
computational tools, like docking and free-energy calculations. In this review, 
we revised the computational strategies utilized so far, for the 
structure-function relationship studies concerning the plasmepsin family, with 
special focus on the recent advances in the improvement of the linear 
interaction estimation (LIE) method, which is one of the most successful 
methodologies in the evaluation of plasmepsin-inhibitor binding affinity.