Cysteine proteases play numerous and extremely important roles in the life
cycle of parasitic organisms with medicinal importance. From general catabolic
functions and protein processing, cysteine proteases may be key to parasite
immunoevasion, excystment/encystment, and cell and tissue invasion. Parasite cysteine
proteases are unusually immunogenic and have been exploited as serodiagnostic
markers and vaccine targets. The research focused on the development of new drugs
actives toward this macromolecular target is an important task, where the rational
design is considered as a critical step on it. The discovery of new drugs is a complex
and multidisciplinary process, which includes an in-depth knowledge of organic
chemistry, pharmacology, biochemistry, computer sciences, and others. This process
involves high costs and several scientific fields, leading to the necessity to develop new
processes that involve optimization of molecular modeling applied to the identification
of bioactive molecules. These techniques could increase the probability of obtaining a
rational-designed compound, with high activity and safety, which could be considered
as a potential drug in the future. Thus, the use of computational techniques has become
increasingly common in medical chemistry laboratories due to their low costs and high
correlation with experimental results from assays. A broadly used technique in the
rational design of active compounds is molecular docking of small ligand at the active
site from the biological targets. In this chapter, we will demonstrate in detail different
molecular modeling techniques applied to the development of new inhibitors against
cruzain (Trypanosoma cruzi); falcipain (Plasmodium falciparum); SmHDAC8
(Schistosoma mansoni); nsP2 (Chikungunya virus) enzymes; and others, such as
cathepsin family; caspase family, 3Cpro (Enterovirus 71) and 3CLpro (Coronavirus). Finally, studies have revealed that the application of molecular modeling is a powerful
tool for predicting new active and productive molecules against infectious diseases.
Keywords: Cysteine Proteases, Drug Discovery, Molecular Modeling, Neglected
Tropical Diseases, Virtual Screening.