Exploring actinomycetes natural products to identify potential multi-target inhibitors against Leishmania donovani

Visceral leishmaniasis (VL) is a neglected tropical disease that mainly affects the poor population of the Indian, African, and South American subcontinent. The increasing resistance to antimonial and miltefosine and frequent toxicity of amphotericin B drives an urgent need to develop an anti-leishmanial drug with excellent efficacy and safety profile. In this study, three sequential docking protocols (HTVS, SP, and XP) were performed to screen the secondary metabolites (n = 6519) from the actinomycetes source against five key proteins involved in the metabolic pathway of Leishmania donovani. Those proteins were adenine phosphoribosyltransferase (PDB ID: 1QB7), trypanothione reductase (PDB ID: 2JK6), N-myristoyl transferase (PDB ID: 2WUU), pteridine reductase (PDB ID: 2XOX), and MAP kinase (PDB ID: 4QNY). Although the binding energy of top ligands was predicted using the MM-GBSA module of the Schrödinger suite. SP and XP docking mode resulted in 55 multi-targeted ligands against L donovani. MM-GBSA analysis selected the top 18 ligands with good-binding affinity and the binding-free energy for four proteins, as mentioned earlier, when compared with the miltefosine, paromomycin, and a reference ligand selected for each target. Finally, molecular dynamics simulation, post-MD-binding-free energy (MM-PBSA), and principal component analysis (PCA) proposed three best ligands (Adenosine pentaphosphate, Atetra P, and GDP-4-keto-6-deoxymannose) qualifying the above screening parameters and confirmed as a potential drug candidate to fight against Leishmania donovani parasites.