Cheminformatic evaluation of the multi-protein binding potential of some diselenide derivatives: A plausible drug discovery approach for leishmaniasis

Over twelve million individuals worldwide suffer from leishmaniasis, and an additional billion people are at risk in places where the disease is prevalent. This work was motivated by the lack of vaccination against leishmaniasis and the shortcomings of current anti-leishmanial treatments. Large compound libraries can be screened using computational methods, which can also be used to analyze pharmacokinetic features, explore protein–ligand interactions, and quickly, accurately, and precisely create novel pharmacological entities. Virtual docking screening was performed to assess the multi-protein targeting capability of certain diselenides using four Leishmania protein targets—2XOX, 3SPX, 5ZWY, and 6K91. Following the Lipinski filter's screening of a subset of analogues, density functional theory (DFT), molecular dynamics (MD) simulation analysis, and ADMET profiles were used to profile the lead compounds. The overall average binding affinity of ligands to target proteins is as follows: 3SPX (− 184.998 kcal/mol) > 6K91 (− 180.114 kcal/mol) > 2XOX (− 176.581 kcal/mol) > 5ZWY (− 157.198 kcal/mol). The focus is on ligands that target all investigated proteins with binding scores greater than the average binding scores for the proteins as a whole for which seven compounds were identified that also showed higher MolDock scores than both reference drugs (Miltefosine and Pentamidine). Further screening showed four compounds (4, 7, 25, and 26) passed Lipinski’s test, making them orally bioavailable with excellent ADMET properties that compared well to both reference medications. The DFT analysis and MD simulation results indicate these compounds' favorability, stability, and reactivity in binding to the studied targets, 3SPX and 6K91 with 25_3SPX and 4_6K91 showing the highest binding free energy (MM-GBSA) of − 88.35 kcal/mol and − 90.29 kcal/mol respectively. Conclusively, the chosen diselenides could be developed as prospective anti-leishmanial pharmacological compounds or as useful scaffolds for creating more potent anti-leishmanial drugs.