In-silico Screening and Identification of Novel Trypanothione Reductase Inhibitor from Leishmania

Abstract

The negative effects of leishmanicidal medications are numerous, and drug resistance to all of them has been observed. As a result, new medication development and the identification of novel therapeutic targets are critical. Leishmania major trypanothione reductase (Lm-TR), a NADPH-dependent flavoprotein oxidoreductase critical for thiol metabolism, is required for parasite viability.  Since it lowers trypanothione, a chemical required by Leishmania's tryparedoxin/tryparedoxin peroxidase system to neutralise hydrogen peroxide (H2O2) produced by host macrophages during infection, this enzyme is essential for parasite survival in the host. Because it is not found in the mammalian host, this enzyme is a promising target for novel anti-leishmania medicines. A three-dimensional model of Lm-TR was created using I-TASSER server. Virtual screening of about 5000 sigma aldrich compounds, acquired from the ZINC database, was carried out using Autodock vina tool. Top ten compounds were tabulated based on binding affinity.  The molecules with the ids ZINC04245710 and ZINC03869768 had the highest binding affinities of -11.4 and -11.2 kcal/mol, respectively. These compounds had the maximum binding affinity and the appropriate amount of hydrogen bonds. These molecules may be able to efficiently block the activity of the target enzyme (Lm-TR) and so serve as novel agents to combat cutaneous leishmaniasis. In search for new anti-Leishmania medications that are more effective and less cytotoxic, these molecules may provide a good starting point for a hit-to-lead procedure.