Toward New Antileishmanial Compounds: Molecular Targets for Leishmaniasis Treatment

Abstract

The leishmaniases are a group of diseases caused by protozoan parasites—Leishmania sp. Leishmaniasis is classified among the 20 neglected diseases by WHO. Although the disease has been known for more than 120 years, the number of drugs used for the treatment is still limited to 5–6. The first-line drugs against leishmaniasis are pentavalent antimonials, which were introduced to the treatment 70 years ago—despite all their side effects. Molecular targets are becoming increasingly important for efficacy and selectivity in postgenomic drug research studies. In this chapter, we have discussed potential therapeutic targets of antileishmanial drug discovery such as pteridine reductase (PTR1), trypanothione reductase (TR), N-myristoyltransferase (NMT), trypanothione synthetase (TryS), IU-nucleoside hydrolase, and topoisomerases, enzymes and their inhibitors reported in the literature.

Identification of Potential Leishmania N-Myristoyltransferase Inhibitors from Withania somnifera (L.) Dunal: A Molecular Docking and Molecular Dynamics Investigation

“…Molecular docking has been employed in multiple studies to create new antiparasitic medications while considering a variety of targets to find new Leishmania treatments [ 8 ]. Discovering new leishmaniasis treatments is made more enticing by molecules implicated in parasite-specific metabolic processes [ 9 ]. The affection of this kind of target implies the death of the parasite and the control of the infection [ 5 ].…”

“…Targeting specific molecular pathways is a common approach in rational drug design and discovery for developing such leishmaniasis-treating compounds. Pteridine reductase, trypanothione reductase, N-myristoyltransferase (NMT), trypanothione synthetase, inosine-uridine nucleoside hydrolase, and topoisomerases are just a few of the more than 21 potential therapeutic targets of antileishmanial drug discovery that have been reported in the literature and gathered in a book chapter [ 9 ].…”

“…In summary, in rational antileishmanial drug design and discovery, targeting particular biochemical pathways was found to be a typical strategy for creating leishmaniasis-treating molecules. In order to screen molecules from both natural and synthetic sources, more than 21 molecular targets were used [ 9 ]. The structure-guided creation of new lead compounds discovered in high-throughput screening efforts aimed at L. major and L. donovani NMT has led to the identification of effective inhibitors [ 9 , 36 ].…”

“…In order to screen molecules from both natural and synthetic sources, more than 21 molecular targets were used [ 9 ]. The structure-guided creation of new lead compounds discovered in high-throughput screening efforts aimed at L. major and L. donovani NMT has led to the identification of effective inhibitors [ 9 , 36 ]. These newly discovered Leishmania NMT inhibitors did not possess the same cellular activity as the enzyme against Leishmania donovani axenic amastigotes, a fact that has been explained by the restricted cellular absorption related to the basic nature of the compounds [ 19 ].…”