Exploration of membrane-bound ecto-phosphatase to identify potential therapeutic target for leishmaniasis

Leishmaniasis, caused by leishmanial parasites, is a major health concern worldwide that emphasizes on the exploration of novel therapeutic targets. Membrane-bound ecto-phosphatase of Leishmania donovani (LdMAcP) is essential for parasite virulence and absence of its ortholog in human makes it an attractive drug target. Hence, LdMAcP was cloned and purified to homogeneity that exhibited optimal catalytic efficiency at acidic pH. Analysis of secondary structure established the presence of appropriate secondary structural content with more α-helices, whereas quenching studies delineated the tryptophan residues to be predominantly situated within the hydrophobic regions. Additionally, LdMAcP elicited immune responses by upregulating pro-inflammatory cytokines and nitric oxide production. Structural studies revealed that LdMAcP shares a common α/β fold with other HAP superfamily members, while docking studies displayed binding of its inhibitor sanguinarine to the catalytic pocket with superior affinity than pNPP. Molecular dynamics simulations confirmed that LdMAcP complexes with pNPP and sanguinarine demonstrate enhanced stability compared to the apo form of the enzyme. Further analysis showed LdMAcP-sanguinarine complex to possess more negative binding energy as compared to its complex with pNPP. Altogether, the study underscores comprehensive insight of structural and immunomodulatory features of LdMAcP, offering its potential therapeutic application against leishmaniasis.