Computational evaluation of the inhibitory potential of some urea, thiourea, and selenourea derivatives of diselenides against leishmaniasis: 2D-QSAR, pharmacokinetics, molecular docking, and molecular dynamics simulation

Abstract

Leishmaniasis affects more than twelve million people globally and a further one billion people are at risk in leishmaniasis endemic areas. The lack of a vaccine for leishmaniasis coupled with the limitations of existing anti-leishmanial therapies prompted this study. Computational techniques have profound applications in screening large libraries of compounds, studying protein-ligand interactions, analyzing pharmacokinetic properties, and designing new drug entities with great speed, accuracy, and precision. This study was carried out to evaluate the anti-leishmanial potential of some diselenides by quantitative structure-activity relationship, pharmacokinetics analysis, density functional theory, molecular docking, and molecular dynamics simulation. The built quantitative structure-activity relationship model was validated (R2train = 0.7128, R2test = 0.6110, Q2LOO = 0.5018) with compounds 6 and 12 having the highest and the least predicted inhibitory activity values of 5.8335 and 4.7998 respectively. Only compounds 7 and 26 passed the drug-likeness test performed on the eight diselenides with relatively higher pEC50. The selected diselenides (7 and 26) showed good pharmacokinetic properties and bound more strongly with the target protein (6K91) than the reference drug (Pentamidine). The results of the studies; density functional theory and molecular dynamics simulation suggest the reactivity, favourability, and stability of the tested compounds in the order; compound 26 > compound 7 > Pentamidine. Conclusively, the selected diselenides could be developed as potential anti-leishmanial drug molecules and/or as useful scaffolds for designing superior anti-leishmanial agents.