Molecular Docking Studies on Eudesmane Sesquiterpenes as Potential Anti-leishmanial Agents

Abstract

In this study, potential inhibitors against Leishmania were identified by docking 30 bioactive compounds from the methanol extract of Solanum erianthum leaves with key Leishmania protein targets. Among the screened compounds, six demonstrated strong binding affinities, with docking scores ranging from −9.2 to −11.4 kcal/mol, particularly against enzymes like trypanothione reductase and arginase, which are crucial for Leishmania’s survival. Experimental validation using in vitro assays confirmed the inhibitory activity of the top three compounds, showing IC50 values between 10 to 25 µM. The findingssss suggest that compounds from Solanum erianthum have the potential to act as lead inhibitors for Leishmania proteins, especially with binding affinity values 30–50% higher than standard inhibitors. Further experimental tests, including enzyme inhibition assays and Leishmania-infected animal models, will be conducted to evaluate their in vivo efficacy. Lead optimization, including structural modifications, is recommended to enhance potency, with a focus on improving pharmacokinetic properties. Visual representations, including protein-ligand interaction diagrams, demonstrated strong hydrogen bonding and hydrophobic interactions, which are critical for the compounds' inhibitory effects.

This study evaluated eudesmane sesquiterpenes as potential therapeutic agents for leishmaniasis, a neglected tropical disease. Nineteen eudesmane-type sesquiterpenes were docked against key target proteins involved in leishmanial glycolysis and polyamine salvage pathways using SwissDock. The binding energies of these compounds were compared to the standard drugs amphotericin B, pentamidine, and miltefosine. Additionally, their drug-likeness and toxicological profiles were assessed using SwissADME and admetSAR. Notably, pterodontic periodontic acid exhibited binding energies comparable to pentamidine against GAPDH (1A7K) and aldolase (1EPX). Similarly, 4α,15-epoxy-eudesmane-1β,6α,11-triol and eudesmane ethyl ester demonstrated binding energies comparable to miltefosine against phosphoglucose isomerase (PGI, 1Q50). Vulgarin and proximadiol outperformed miltefosine, pentamidine, and amphotericin B in binding to transketolase (1R9J).All five compounds met Lipinski's criteria for drug-likeness, and toxicity predictions indicated they are weak hERG channel inhibitors, non-carcinogenic, and non-AMES toxic. These findings suggest that these eudesmane sesquiterpenes are promising candidates for anti-leishmanial drug development.