Chemoinformatics Strategies for Leishmaniasis Drug Discovery

Abstract

Leishmaniasis is a fatal neglected tropical disease (NTD) that is caused by more than 20 species of Leishmania parasites. The disease kills approximately 20,000 people each year and more than 1 billion are susceptible to infection. Although counting on a few compounds, the therapeutic arsenal faces some drawbacks such as drug resistance, toxicity issues, high treatment costs, and accessibility problems, which highlight the need for novel treatment options. Worldwide efforts have been made to that aim and, as well as in other therapeutic areas, chemoinformatics have contributed significantly to leishmaniasis drug discovery. Breakthrough advances in the comprehension of the parasites’ molecular biology have enabled the design of high-affinity ligands for a number of macromolecular targets. In addition, the use of chemoinformatics has allowed highly accurate predictions of biological activity and physicochemical and pharmacokinetics properties of novel antileishmanial compounds. This review puts into perspective the current context of leishmaniasis drug discovery and focuses on the use of chemoinformatics to develop better therapies for this life-threatening condition.

Discovery of new potent lysine specific histone demythelase-1 inhibitors (LSD-1) using structure based and ligand based molecular modelling and machine learning

“…, pharmacophore model(s)). 37–39 In addition to crystal structures, which are the main source of structural information, 40 virtual complexes obtained by docking potent ligands into corresponding receptors were also employed to extract valid structure-based pharmacophores. 40,41…”

“…Structure-based pharmacophore modelling depends on interactions within ligand/receptor complexes to extract binding features and arrange them in 3D context (i.e., pharmacophore model(s)). [37][38][39] In addition to crystal structures, which are the main source of structural information, 40 virtual complexes obtained by docking potent ligands into corresponding receptors were also employed to extract valid structure-based pharmacophores. 40,41 In this approach, a small, diverse set of potent molecules are either co-crystallized within the target protein or docked into the binding site of the target.…”

Development of Novel Anti-Leishmanials: The Case for Structure-Based Approaches

“…These approaches to the discovery of therapeutics against NTDs including the development of novel anti -leishmanials have made remarkable progress [28][29][30]. SBDD approaches using the structures of leishmanial Cysteine Protease B (CPB; essential for parasite survival in the host), Type 2 NADH dehydrogenase [NDH2] (a mitochondrial enzyme that converts NADH to ubiquinone and is crucial for parasite survival), Nucleoside Diphosphate Kinase (crucial for maintaining intracellular NTP levels), and Topoisomerase-II (catalyzes single-stranded breaks in DNA during gene replication and transcription) have led to the identification of novel inhibitors (Figure 4) [28,[31][32][33][34][35][36]. It is pertinent, however, to emphasize that these studies have not yet resulted in the development of candidates that have reached any clinical trial stage but are primary steps towards a rationale-driven approach for novel anti-leishmanials.…”

A QSAR Study for Antileishmanial 2-Phenyl-2,3-dihydrobenzofurans †

“…The use of computational methods to aid in solving different problems in drug discovery pipelines is becoming more and more important, particularly with the advent of artificial intelligence [13][14][15][16][17][18][19]. In silico approaches have, therefore, been applied for the rational design and discovery of potential drugs against Leishmaniasis [20][21][22][23][24][25]. Due to the limited knowledge about validated targets for Leishmaniasis, ligand-based methods investigating structureactivity relationships (SARs) may represent a suitable approach.…”