Abstract
Leishmaniasis is a vector-borne parasitic disease caused by Leishmania spp., that contributes substantially to global morbidity. Considering the toxicity, drug resistance and limited efficacy of current therapies, drug repositioning represents an efficient approach for identifying novel antileishmanial agents from existing pool of drugs. In this context, we evaluated antileishmanial potential of Linsitinib, a known tyrosine kinase inhibitor and an anticancer molecule in advance stages of development. Linsitinib demonstrated potent anti-proliferative activity with IC50 values of 1.308 ± 0.1267µM against L. donovani and 3.865 ± 0.9688µM against L. mexicana promastigotes with marginal toxicity against human THP-1 macrophages at same doses. Linsitinib exhibited pronounced anti-amastigote activity with IC50 values of 0.8788µM and 1.014µM, against L. donovani and L. mexicana respectively. Selectivity index (SI) values of 51.77 (L. donovani) and 44.87 (L. mexicana) further corroborated the selective activity of Linsitinib, against Leishmania amastigotes over host cells. To ascertain the mechanistic details of in vitro inhibition, in silico studies were performed against, N-myristoyltransferase (NMT) enzyme, as a key parasite target and human PI3K to establish host-directed immunomodulatory activity. In silico molecular docking and molecular dynamics simulations demonstrated stable binding of Linsitinib with both targets, supported by hydrogen bonding, hydrophobic interactions and favorable stability parameters (RMSD, RMSF, radius of gyration and solvent-accessible surface area). Overall, Linsitinib demonstrates marked inhibition of Leishmania parasites, and this activity is supported through NMT-mediated disruption of parasite viability and PI3K/Akt-driven host immune modulation, supporting its candidacy as a dual-targeting broad-spectrum therapeutic alternative for leishmaniasis.