Exploration of novel azole-quinoline hybrids as LdNMT inhibitors using in-silico approach; molecular docking, DFT, molecular dynamics simulations, MMGBSA and ADMET

Leishmania donovani, the causative agent of visceral leishmaniasis (VL), is prevalent in Brazil, East Africa, and India. The treatment options for VL are currently limited and are often associated with adverse effects, highlighting the urgent need for the development of safer and more effective therapies. N-myristoyltransferase (NMT) is one of the few genetically proven therapeutic targets for the development of drugs against kinetoplastid parasitic protozoa. In this study, we performed high-throughput virtual screening (HTVS) of designed 108 azole-quinoline hybrid compounds using molecular docking against LdNMT. The molecular docking results indicated that compounds 47 and 50, two strong inhibitors, had binding energies of −9.02 and −8.13 kcal/mol, compared to control drug (DDD85646), which had a binding energy of −4.38 kcal/mol. Furthermore, these lead compounds were subjected to molecular dynamics (MD) simulations to determine the stability of the ligand with LdNMT under physiological conditions. Then, the stability of both complexes revalidated through the MMGBSA method that unfolded the free binding energy −100.83 kcal/mol, and −84.31 kcal/mol for compounds 47, and 50 respectively, which delivered reliable binding stability with the protein. Density functional theory (DFT) analysis was used to explore the chemical reactivity of the lead compounds. This study found that most of the compounds adhered to Lipinski's rule of five with minimal violations, and their ADMET properties were within acceptable ranges compared with the standard drug. The in silico results suggested that azole-quinoline hybrid, particularly compounds 47 and 50, could be promising inhibitors of LdNMT, potentially serving as effective therapeutic agents for VL treatment.