Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling
Date
2023
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
Pharmaceuticals
Abstract
The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort
to find new leads. The study combined In silico and in vitro approaches to identify novel potential
synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT).
The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite’s membrane
fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue
in the human host and its conserved nature among all Leishmania parasites makes it a viable target
for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 µM were
used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated
model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled
three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with
binding energies ranging from −7.5 to −8.7 kcal/mol were identified as potential hit molecules. Three
compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of −8.7, −8.2, and −8.0 kcal/mol, lower than 22,26-azasterol (−7.6 kcal/mol), a known
LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and
molecular mechanics Poisson–Boltzmann surface area calculations showed that the residues Asp25 and
Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial
activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of
the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 µM (STOCK6S-06707), 23.5 ± 1.1 µM (STOCK6S-84928), and
118.3 ± 5.8 µM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920
inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 µM and 18.1 ± 1.4 µM, respectively.
The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.
Description
Research Article
Keywords
Leishmania donovani;, sterol methyltransferase, pharmacophore
Citation
Citation: Sakyi, P.O.; Kwofie, S.K.; Tuekpe, J.K.; Gwira, T.M.; Broni, E.; Miller, W.A., III; Wilson, M.D.; Amewu, R.K. Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling. Pharmaceuticals 2023, 16, 330. https://doi.org/ 10.3390/ph16030330