Leishmaniasis, a group of protozoan parasitic infections, ranks among the top 10 neglected tropical diseases and is the second most dreadful infection following malaria [1,2]. According to the current report by WHO, the disease manifestations are predominant in eight major countries of tropical as well as subtropical regions, registering between 0.7 and 1.3 million new leishmaniasis cases and annual deaths between 26,000 and 65,000 [[3], [4], [5]]. This vector-borne zoonotic infection is caused by an obligate intracellular parasite of the genus Leishmania, with more than 20 species causing various clinical manifestations, ranging from self-healing cutaneous form to the most fatal visceral form. Even after extensive drug discovery and development efforts, a fully effective treatment for leishmaniasis remains elusive. Unfortunately, till now, there are no vaccines or truly effective drug therapies available for any form of leishmaniasis [6,7]. The current treatment strategy for leishmaniasis prioritizes pentavalent antimonials as the first-line drug, whereas amphotericin B, miltefosine, and paromomycin (second-line therapy) are reserved for cases where the first-line drug is ineffective or has developed resistance [8,9]. However, the pitfalls associated with available treatment alternatives, such as adverse toxicity (hepatotoxicity, nephrotoxicity, cardiotoxicity, ototoxicity), prolonged treatment courses, drug resistance, high cost with limited efficacy, and long cold chain treatment ultimately highlight the need for a new potent drug candidate to fight against this dreadful infection [10,11].

The effective development of leishmaniasis therapeutics presents a significant hurdle due to the remarkable adaptability and intricate genetic plasticity in the parasitic biological system [6,12]. Extensive research has been dedicated to the identification of optimal drug targets for novel drug discovery. However, the critical concern persists in finding the therapeutic target with the least or no homology within the host cell, thus ensuring that inhibitors selectively target the parasitic proteins without inflicting harm upon the host. Further, considering the complex parasite's lifecycle, the ideal drug target must be indispensable for parasitic survival [[13], [14], [15]]. In this regard, various pathways such as the glycolysis pathway, purine salvage pathways, polyamine biosynthesis, DNA replication, and sterol biosynthetic pathways have been rigorously explored to dig out the novel druggable targets [[16], [17], [18], [19]]. Out of all the aforementioned pathways, sterol biosynthesis has grabbed the greater attention of the research community due to the fact that the pathway's end product, i.e., ergosterol, is critical for the membrane biosynthesis, fluidity, integrity, mitochondrial homeostasis, as well as aggravating the infection in the host milieu [20,21]. Even the recent compelling development reported by Jin et al. [22] emphasizes the pivotal understanding of ergosterol synthesis within a unicellular parasite that offers a promising avenue for the creation of next-generation, highly effective leishmaniasis treatments. Differing from human counterparts, who employ cholesterol, Leishmania parasites rely on ergosterol as an essential building block for their cell membranes, and this makes the sterol metabolic enzymes a plausible drug target. Interestingly, Sterol C-24 methyl transferase (SMT), an enzyme of the last commitment step in the ergosterol biosynthesis pathway, catalyzes the S-adenosylmethionine-mediated transfer of methyl groups at C-24 in steroid intermediates [23,24]. Another well-known enzyme, the Sterol 14α-demethylase (SDM), catalyzes the formation of 4,4-dimethylcholesta-8(9),14,24-triene-3b-ol from lanosterol [25,26]. Unlike other enzymes of this pathway, SMT has no homology, and SDM (15–17%) has minimal homology with the human host, causing minimal toxicity. Moreover, these two essential enzymes are critical for parasitic survival and act as virulence factors in exacerbating the disease condition, and thus, underscore superior potential as a druggable target for advancing leishmaniasis treatment [27,28].

A wide range of molecules encompassing various structural classes (both natural and synthetic sources), such as azoles, imidazoles, sulphonamides, terpenoids, etc., have been reported as inhibitors of SDM and SMT proteins [[29], [30], [31]]. These molecules show exceptional anti-parasitic potential complemented with a safe profile and significant efficacy in in vivo settings. Interestingly, in recent times, the amalgamation of computational and experimental approaches has come up as the new state-of-the-art against traditional drug discovery, providing new potential chemical scaffolds [[32], [33], [34]]. Capitalizing on the synergistic power of computational and experimental methodologies, the present review article highlights the utilization of computer-aided drug discovery tools for detailed insight into the biology of SDM and SMT inhibitors. A comprehensive literature review performed using various search engines such as PubMed, Scopus, Science Direct, Google Scholar, etc., identifies a broad spectrum of known inhibitors of both SDM and SMT proteins from various organisms. Further, molecular docking studies of these known inhibitors against the SDM and SMT proteins of L. donovani were performed using AutoDock Vina. The meticulous understanding of enzyme-inhibitor interactions and visualizing precise binding poses unveils the intricate molecular mechanisms through which inhibitors exert their influence (Fig. 1). Ultimately, this review article furnishes a thorough understanding of targeting SDM and SMT, two pivotal proteins in L. donovani, as compelling therapeutic targets, thereby contributing to the development of innovative anti-leishmanial chemotherapy.