Homology Modeling, Design of Ligands, and Molecular Docking Identify Potential Inhibitors of 24-Sterol Methyltransferase.

The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. 24-sterol methyltransferase (SMT) is vital for the synthesis of ergosterols, the main constituents of cellular membranes. So far, mammals have not been shown to possess SMT or ergosterols, making the pathway a prime candidate for drug discovery. The structural model of SMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors virtual screening, scaffold hopping, and fragment-based design. Altogether, six potential novel inhibitors were identified with binding energies ranging from -7.0 to -8.4 kcal/mol with e-LEA3D using 22,26-azasterol and - obtained from scaffold hopping the ChEMBL, DrugBank, PubChem, ChemSpider, and ZINC15 databases. These ligands showed comparable binding energy to 22,26-azasterol (-7.6 kcal/mol), the main inhibitor of SMT. Moreover, all the compounds had plausible ligand efficiency-dependent lipophilicity (LELP) scores above 3. The binding mechanism identified Tyr92 to be critical for binding, and this was corroborated molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The ligand was predicted to possess antileishmanial properties with a probability of activity (Pa) of 0.362 and a probability of inactivity (Pi) of 0.066, while and possessed dermatological properties with Pa values of 0.205 and 0.249 and Pi values of 0.162 and 0.120, respectively. Structural similarity search DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the compounds could be explored as potential antileishmanial agents.