Multi-protein targeting potential of some urea, thiourea, and selenourea derivatives of diselenides in leishmaniasis: molecular docking screening, oral bioavailability analysis, ADMET profiling, and molecular dynamics simulation

Abstract

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, analysing pharmacokinetic properties, and designing new drug entities with great speed, accuracy, and precision. This study was carried out to evaluate the multi-protein targeting potential of some diselenides by virtual docking screening using four Leishmania protein targets (2XOX, 3SPX, 5ZWY, and 6K91). Selected analogues were screened using Lipinski filter, and the resulting lead compounds were profiled by ADMET, density functional theory (DFT), and molecular dynamics (MD) simulation analyses. The overall average binding affinity of ligands to target proteins follow the order: 3SPX (-184.998) > 6K91 (-180.114) > 2XOX (-176.581) > 5ZWY (-157.198). Also, both reference drugs (Miltefosine and Pentamidine) showed relatively weaker interactions with the studied receptors. Only compounds 4, 7, 25, and 26 passed the drug-likeness test performed on the seven diselenides with relatively higher multi-protein binding potential. These compounds also showed good pharmacokinetic properties and compared excellently to both reference drugs. The results of the DFT study and MD simulation, suggest the reactivity, favourability, and stability of these compounds in their binding with tested targets; 3SPX and 6K91. Conclusively, the selected diselenides could be developed as potential anti-leishmanial drug molecules and/or as useful scaffolds for designing superior anti-leishmanial agents.