Thiadiazine-thiones as inhibitors of leishmania pteridine reductase (PTR1) target: investigations and in silico approach.

Leishmaniasis is a widespread parasitic disease and is one of the major public health concerns in developing countries. Many drugs have been identified for leishmania as targets, but the potential toxicity and long-term treatment remain the most significant problems in terms of further development. The present study employed physicochemical investigations, structure-based virtual screening, ADMET analysis, molecular dynamics simulation, and MM-PBSA, to identify potential compounds for Leishmania. We evaluated 30,926 natural products from the NPASS database, and four potentials passed the pharmacokinetic ADMET studies and were verified using the molecular docking approach. Molecular docking results showed good binding interaction of the compounds with the active site of leishmania pteridine reductase enzyme PTR1, with compound TTC1 showing FRED and Autodock binding energies of -10.33 and -10.94, respectively, which were comparable with the antileishmania drugs of Allopurinol, Miltefosine and the original ligand, methotrexate. TTC1 compound was found to be favorable for hydrophobic interaction with PTR1. In addition, the physicochemical properties of the compounds were studied using the SwissADME web server. All compounds followed Lipinski's rule of five and can be considered as good oral candidates. The analysis of the 100 ns molecular dynamics simulation results based on the best-docked TTC1 with PTR1 receptor demonstrates stable interactions, and the complex undergoes low conformational fluctuations. The average of the calculated binding free energy of the TTC1-1e7w complex is (-68.67 kJ/mol), and the result demonstrated that the TTC1 promoted stability to the Leishmania-PTR1 complex. The potential compounds can be further explored for their antileishmanial activity.Communicated by Ramaswamy H. Sarma.