A comprehensive review of targeting sterol 14α-demethylase and sterol C-24 methyl transferase, two pivotal proteins in Leishmania, as compelling therapeutic targets.

Leishmaniasis, a neglected tropical disease, poses a significant global health challenge mainly in tropical and subtropical areas. The limited treatment alternatives, coupled with significant associated toxicity, necessitate the requirement to identify new chemical scaffolds with reduced toxicity and improved efficacy. The two essential enzymes of the sterol biosynthetic pathway, Sterol C-24 methyl transferase (SMT) and Sterol 14α-demethylase (SDM), hold great promise as plausible drug targets due to their essentiality for parasite survival and virulence, along with exhibiting minimal homology with human counterparts. The present review discusses the importance of targeting leishmanial SDM and SMT proteins in the perquisite for anti-leishmanial drug discovery. We have performed a comprehensive search using various databases and created a small-molecule sterol inhibitor library, and by utilizing computational biology approaches, we tried to meticulously understand enzyme-inhibitor interactions of the library molecules with the leishmanial SMT and SDM proteins. Information pertaining to the chemical structure of the inhibitors, binding affinities, and interacting residues with both the proteins that drive their mode of action towards them has been elucidated. Thus, this review addresses inclusive information on Leishmanial SMT and SDM proteins, which can aid in unraveling new molecules to fight against the deadly parasitic infection by leveraging computational tools.