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

Abstract

The therapeutic challenges pertaining to leishmaniasis due to reported chemoresistance and toxicity necessitate the need to explore novel pathways to identify plausible inhibitory molecules. Leishmania donovani 24-sterol methyltransferase (LdSMT) is vital for the synthesis of ergosterols, the main constituents of Leishmania 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 LdSMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors via virtual screening, scaffold hopping, and de-novo 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 S1–S4 obtained from scaffold hopping via 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 LdSMT. 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 via molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The ligand A1 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 A5 and A6 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 via DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the de-novo compounds could be explored as potential antileishmanial agents.

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

“…The pharmacophore model was then used to screen a library of 95,630 synthetic compounds from InterBioScreen limited. Ligands with pharmacophore fit scores above 50 were docked against a previously modelled structure of Ld SMT [ 29 , 38 ]. The selected hit compounds were evaluated via physicochemical, pharmacological, and toxicity profiles, as well as biological activity predictions, MD simulations, and MM/PBSA computations.…”

“…The three-dimensional (3D) structure of Ld SMT previously elucidated using Modeller version 10.2 [ 29 , 38 ] was used. Energy minimisation of the target protein was carried out by employing the Optimized Potential for Liquid Simulations (OPLS)/All Atom force field [ 39 ] via the Groningen Machine for Chemical Simulations GROMACS version 2018 (GROMACS 2018) [ 40 , 41 ].…”

“…The amino acid residues and the probable volume and area of the binding site of the modelled protein were determined using the Computed Atlas of Surface Topography of proteins (CASTp) [ 44 ] and Biovia Discovery Studio Visualizer v.19.1.0.18287 [ 42 ], as indicated in a previous study [ 29 ].…”

“…The charge, hydrogen bond network, and histidine protonation state of the protein were assigned after pdbqt conversion [ 32 ]. The grid box size (91.445 × 73.502 × 78.352) Å 3 with the centre (72.200, 58.009, 13.302) Å was used with an exhaustiveness of 8 [ 29 ].…”

“…Similarly, ezetimibe, imipramine, and simeprevir ( Figure 1 ) have shown promising inhibitory activity against L. donovani by making morphological changes to the plasma and mitochondrion membranes with IC 50 of 30, 28.6, and 51.49 μM, respectively [ 26 , 27 , 28 ]. A fragment-based de novo design was used to predict potential inhibitors against L. donovani sterol methyltransferase ( Ld SMT) [ 29 ]. Though several hit compounds have been identified targeting this enzyme, only a few progressed to the clinical evaluation stage [ 30 , 31 , 32 , 33 , 34 ].…”