Leishmania mexicana Trypanothione Reductase Inhibitors: Computational and Biological Studies

Abstract

Leishmanicidal drugs have many side effects, and drug resistance to all of them has been documented. Therefore, the development of new drugs and the identification of novel therapeutic targets are urgently needed. Leishmania mexicana trypanothione reductase (LmTR), a NADPH-dependent flavoprotein oxidoreductase important to thiol metabolism, is essential for parasite viability. Its absence in the mammalian host makes this enzyme an attractive target for the development of new anti-Leishmania drugs. Herein, a tridimensional model of LmTR was constructed and the molecular docking of 20 molecules from a ZINC database was performed. Five compounds (ZINC04684558, ZINC09642432, ZINC12151998, ZINC14970552, and ZINC11841871) were selected (docking scores −10.27 kcal/mol to −5.29 kcal/mol and structurally different) and evaluated against recombinant LmTR (rLmTR) and L. mexicana promastigote. Additionally, molecular dynamics simulation of LmTR-selected compound complexes was achieved. The five selected compounds inhibited rLmTR activity in the range of 32.9% to 40.1%. The binding of selected compounds to LmTR involving different hydrogen bonds with distinct residues of the molecule monomers A and B is described. Compound ZINC12151998 (docking score −10.27 kcal/mol) inhibited 32.9% the enzyme activity (100 µM) and showed the highest leishmanicidal activity (IC50 = 58 µM) of all the selected compounds. It was more active than glucantime, and although its half-maximal cytotoxicity concentration (CC50 = 53 µM) was higher than that of the other four compounds, it was less cytotoxic than amphotericin B. Therefore, compound ZINC12151998 provides a promising starting point for a hit-to-lead process in our search for new anti-Leishmania drugs that are more potent and less cytotoxic.

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

“…Thus, producing leishmanicidal medications, agents that impact arginine transport into Leishmania cells, block polyamine production, trypanothione reduction, and elF5A hypusination should be intensively explored to limit the parasite survival [115], [160]. Drugs like thioether derivative, immunomodulator, pyrrolopyrimidine and 5-6-5 imidazole-phenyl-thiazole -helix-mimetic scaffolds, resveratrol analogues, aminoguanidine hydrazones (AGH) and thiosemicarbazones (TSC), Masticadienonic acid, and 3-Methoxycarpachromene are being repurposed to target these enzymes [100], [103], [106], [108]. Besides repurposed drugs, multiple herbal extracts are being discovered to be utilized against Leishmania infection including Corchorus capsularis, Candida albican, pelargonium sidoides, glycorhyza glabra, Piper betle, Tinospora sinensis etc [107],…”

“…mexicana medicines [103]. According to computer simulations, aminoguanidine hydrazones (AGH) and thiosemicarbazones (TSC) showed satisfactory anti-leishmanial efficacy.…”

Benzimidazole Derivatives as New and Selective Inhibitors of Arginase from Leishmania mexicana with Biological Activity against Promastigotes and Amastigotes

“…The assays were made by triplicate in 3 independent experiments. CC 50 values of Amphotericin B, Miltefosine and Glucantime were taken from a previous study [28] performed under the same conditions by our research group.…”

2,3-Dihydroquinazolin-4(1H)-one as a New Class of Anti-Leishmanial Agents: A Combined Experimental and Computational Study

“…The 3b ligand binding site occupies a different binding site than 3a consisting of Gly 11 , Gly 13 , Ser 14 , Gly 15 , Gly 16 , Ala 46 , Gly 49 , Gly 50 , Thr 51 , Cys 52 , Val 53 , Ala 159 , Thr 160 , Gly 161 , Ser 162 , Arg 287 , Arg 290 , Gly 326 , Asp 327 , Leu 334 , Thr 335 , and Ala 338 (Figure 9). Here, Cys52 is a catalytic residue, while the FAD-binding domain consists of 1-160 residues, the NADPH-binding domain compasses 161 to 288 amino acids [71]. Aryl-substituted imidazole has been found to bind to the same binding site in TPR as 3a and 3b, where one ligand showed binding energy of −11.30 kcal/mol and dissociation of 5.19 nM [72].…”

“…Both complexes show RMSD and RMSF changes in the 72-94 amino acids region. However, the active sites of both ligands don't overlap, and the primary binding In a previous study, 600,000 ZINC compounds were screened against leishmanial trypanothione reductase 20 potential ligands with binding energies of −10.27 to −5.29 kcal/mol were reported [71]. Fucosterol was found to bind trypanothione reductase with a binding energy of −8.0 kcal/mol.…”