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. 1. Introduction More than 40% of the world’s population lives with some risk of contracting malaria, with most recent estimates suggesting several hundred millions of clinical cases with 800,000 deaths each year [1]. In humans, the disease is the result of the infection by Plasmodium falciparum (Pf), Plasmodium malariae, Plasmodium ovalae, or Plasmodium vivax. Of these species, Pf is the most lethalm and it is, therefore, the main target for drug intervention. Once the microbe is transmitted to humans by mosquitoes of the anopheles genus, it causes many problems, but most commonly severe, recurring fever attacks [2]. Despite considerable efforts in this field, it has not been possible to develop an efficient vaccine to prevent malaria. The main disadvantages are (i) the increasing resistance of vectors to insecticides and (ii) the emergence of multidrug-resistant variants of Pf to existing antimalarial drugs, with the exception of the artemisinns [3]. Therefore, in the last years, researchers have focused their efforts towards the discovery of more selective and potent drugs [2]. Hemoglobin (Hb)-degrading enzymes of Pf emerge as very promising chemotherapeutic targets, because Hb degradation is a unique and critical process for Pf [2]. During the intraerythrocytic stage of the parasite’s life cycle, this protozoon consumes approximately 75% of the Hb in the infected red blood cell [7, 8], which provides the main source of amino acids for the parasite
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