Harnessing computational methods for uncovering structural insights into Leishmania donovani 3-MST: implications for drug design and target specificity.

3-Mercaptopyruvate sulfurtransferase (3-MST) is an enzyme that plays integral roles in various biological processes. In the realm of Leishmania, the role of 3-MST is less explored. It is a critical player in maintaining oxidative homeostasis in Leishmania during stress for survival. This highlights the potential of Ld3-MST as an appealing drug target. However, recognising structural disparities becomes essential when a protein is present in the host and parasite. This study delves into the structural distinctions between Ld3-MST and Hs3-MST, providing valuable insights with direct implications for drug design. A standout feature of Ld3-MST is the elongated 70 amino acid C-terminal mainly contributing to a lid-like domain above the active site cavity, setting it apart from Hs3-MST. The RMSD analysis shows fluctuation due to the extended tail, while Rg and SASA confirm the open and solvent-accessible nature of Ld3-MST, especially in its active site, suggesting its ability to accommodate larger molecules. PC and FEL analysis reveals unique internal molecular dynamics of Ld3-MST, particularly in its active site. Docking studies demonstrate that Ld3-MST's active site can effectively accommodate molecules, highlighting its potential as a drug target. This comprehensive investigation lays the foundation for developing precise Ld3-MST inhibitors with promising therapeutic applications.

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Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00340-6.