<i>IN SILICO</i> AND <i>IN VITRO</i> STUDIES: TRYPAREDOXIN PEROXIDASE INHIBITOR ACTIVITY OF METHOTREXATE FOR ANTILEISHMANIAL ACTIVITY

Abstract

In order to understand the mechanism of molecular interactions at the active site of Tryparedoxin Peroxidase (Try P), homology modeling and docking studies were performed. We generated a Three-Dimensional (3D) model of target protein based on the Crystal structure of Leishmania Major Try PI (PDB ID: 3TUE) using modeler software. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (Try P). Inhibition of the Tryparedoxin peroxidase interaction has become a new therapeutic strategy in treating leishmaniasis. Docking analysis was carried out to study the effects of methotrexate on Tryparedoxin Peroxidase (TryP). Tryparedoxin peroxidase of Trypanosomatidae family functions as antioxidant through their peroxidase and peroxynitrite reductase activities. The theoretical docking study, conducted on a sample previously reported for anti-cancer properties of Methotrexate at the binding site of 3D models of Tryparedoxin Peroxidase of Leishmania braziliensis (L. braziliensis Try P) examine interaction energy. Our studies indicate that Methotrexate displays potent activity against Try P with lowest binding energy and RMSD values to be -14.5879 Kcal/Mol and 2.0 A. The results of the present study clearly demonstrated the Tryparedoxin Peroxidase inhibitory activity by methotrexate in in silico docking analysis and in vitro assay which contributes towards understanding the mechanism of antileishmanial activity.

Mahanine exerts in vitro and in vivo antileishmanial activity by modulation of redox homeostasis

“…Due to the absence of selenium-dependent glutathione peroxidase, tryparedoxin is one of the major enzymes reported to be a virulent protein in Leishmania to neutralize oxidative insult 31 . Therefore this may be considered as a potent drug target 32 . Ascorbate peroxidase in another major antioxidant enzyme reported to function during oxidative burst for parasite survival 33 .…”

In-Silico Identification of the Best Compound Against <i>Leishmania infantum</i>: High Throughput Screening of All FDA Approved Drugs

“…The "in-silico" analysis which stands for computer-based biological experiments, is a state-of-the-art and accurate method to discover exclusive bioactive compounds, which may represent novel metabolic pathways and/or a powerful affinity to a certain target (42). In this sense, several studies have identified unprecedented molecules for various drug targets in Leishmania, such as pteridine reductase1, tryparedoxin peroxidase and sterol biosynthesis (43)(44)(45)(46)(47)(48), as well as in other single-celled eukaryotes enclosing Toxoplasma gondii, Cryptosporidium hominis, Plasmodium and Trypanosoma cruzi (49)(50)(51). Current in-silico investigation was aimed to screen and predict the anti-leishmanial potency of 3358 FDA-approved compounds against both drug targets in L. infantum in comparison to amphotericin B and glucantime for the discovery of new biochemical molecules.…”