Targeting cysteine proteases from Plasmodium falciparum: A general overview, rational drug design and computational approaches for drug discovery.

The Plasmodium falciparum cysteine proteases, also known as falcipains, are involved in different erythrocytic cycle processes of the malaria parasite, e.g. hydrolysis of host haemoglobin, erythrocyte invasion, and erythrocyte rupture. With the biochemical characterization of four falcipains so far, FP-2 (falcipain-2) and FP-3 (falcipain-3), members of the papain-like CAC1 family, are essential haemoglobinases. They could therefore be referred to as potential anti-malarial drug targets in the search for novel therapies, which could ease the burden caused by the increasing resistance to current anti-malarial drugs. This review provides a summary of the most important results, highlighting the drug design approaches essential for the understanding of the mechanism of inhibition and discovery of inhibitors against cysteine proteases from P. falciparum. Rational and computer-aided drug discovery approaches for the design of promising falcipain inhibitors are described herein, with a focus on a variety of structure-based and ligand-based modeling approaches. Moreover, the key features of ligand recognition against these targets are emphasized. This review would be of interest to scientists engaged in the development of drug design strategies to target the cysteine proteases, FP-2 and FP-3.