Structure and dynamics studies of sterol 24-C-methyltransferase with mechanism based inactivators for the disruption of ergosterol biosynthesis

Abstract

The enzyme sterol 24-C-methyltransferase (SMT) belongs to the family of transferases, specifically to the one-carbon transferring methyltransferases. SMT has been found playing a major role during the production of steroids, especially for the biosynthesis of ergosterol, which is the major membrane sterol in leishmania parasites, causing leishmaniasis. However, SMT and ergosterol are not found in mammals, so, an extensive study has been carried out over the susceptible SMT protein, which is found to be highly conserved among all the Leishmania species and holds a significant anti-leishmanial drug target. To date, there is no computational data available for SMT, due to its highly unexplored profile. In this work, a complete set of structural attributes have been examined through the available computational procedures, along with an attempt to characterize the most capable modeling server available. The exploration ranges from physicochemical characterization, pairwise alignment, secondary structure prediction, to active site detection. With this information, a docking study was carried out to find the compound that best binds into the active site. Moreover, molecular dynamics simulation was conducted to examine the stability of the homology modeled protein and the ligand-enzyme complex. The results indicate that the ligand-enzyme complex is more stable.

Homology Modeling, de Novo Design of Ligands, and Molecular Docking Identify Potential Inhibitors of Leishmania donovani 24-Sterol Methyltransferase

“…The 3BUS template had the least E -value of 6 × 10 −20 and identity of 24.12%. The 3BUS protein has previously been used in modeling the SMT of L. infantum ( Azam et al., 2014 ). Although 3BUS had a low resolution (2.65 Å), it was selected as one of the structures for modeling.…”

Repurposing of FDA‐approved drugs as inhibitors of sterol C‐24 methyltransferase of Leishmania donovani to fight against leishmaniasis

“…SMT inhibitors act by making serious changes in the plasma membrane and mitochondrial membrane of the parasite (Mukherjee et al, 2019). Many existing inhibitors do ammonium or sulfonium function in their side chain resulting in inhibitory action (Azam et al, 2014). In silico studies uses mechanism-based inactivators probing that gives an idea about amino acids and active sites that are targeted by drugs (Azam et al, 2014).…”

“…Many existing inhibitors do ammonium or sulfonium function in their side chain resulting in inhibitory action (Azam et al, 2014). In silico studies uses mechanism-based inactivators probing that gives an idea about amino acids and active sites that are targeted by drugs (Azam et al, 2014). The lack of effective therapeutics against leishmaniasis has necessitated the identification of new drug by drug repurposing approach.…”

Dual RNA-Seq Analysis of Trichophyton rubrum and HaCat Keratinocyte Co-Culture Highlights Important Genes for Fungal-Host Interaction

“…In the present study, we observed the induction of TERG_03102 (log 2 fold change: 2.05) (functional category: metabolic process), which corresponds to the ERG6 gene. This gene encodes the enzyme 24-C-methyltransferase, which participates in ergosterol biosynthesis [ 35 ]. Ergosterol is known to be responsible for fungal plasma membrane fluidity and permeability and it is important for the adequate function of membrane-anchored proteins [ 36 ].…”