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Preliminary investigation of drug re-purposing as a direction towards anti-Leishmanial drug discovery

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Abstract: Leishmaniasis is a vector born neglected tropical disease caused by Leishmania parasites and communicated by the bite of female Phlebotomine sandfly. Leishmaniasis is associated with more than 1 billion cases annually. Some of the pharmacological options for treating the disease are pentavalent antimonial, pentamidine, miltefosine and amphotericin B. Drug repurposing is a strategy of identifying new uses of approved or investigational drugs that are outside the scope of the first medical indication. In the current study, we looked for pharmacological alternatives to treat leishmaniasis, with an emphasis on drug repurposing approach. In-silico studies were carried out with the help of Schrodinger software and ZINC database was used as a source. Trypanothione reductase (PDB-2JK6) was selected as target protein and validated by checking the RMSD before docking studies. The outcomes of the study revealed that some of the compounds were active against the selected target. We selected top 5 hit molecules and the top 1 molecule is 5-methoxy tetrahydro folic acid. All the hydrogen bonding, aromatic and Pi-Pi interactions of the moiety with the surrounded amino-acid exhibited a significant docking score of -14.07 kcal mol, which was almost similar to that of co-crystal ligand -14.60 kcal mol. The top hit molecule was further selected for molecular dynamics study in order to screen out the stability of protein-ligand complex for 5 ns. After completion of the study, it was observed that the test molecule was in the deeper side of the binding pocket of the target protein and reveled its maximum interactions to stabilize the protein-ligand complex. Further, in-vitro and in-vivo evaluation of these compounds will be required in order to conclude that they will be useful for the leishmanial therapy in the future.

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