Sakyi, Patrick O, Broni, Emmanuel, Amewu, Richard K 
ORCID: 0000-0002-4676-436X, Miller, Whelton A, Wilson, Michael D and Kwofie, Samuel Kojo
(2022)
Homology Modeling, <i>de Novo</i> Design of Ligands, and Molecular Docking Identify Potential Inhibitors of <i>Leishmania donovani</i> 24-Sterol Methyltransferase.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY, 12.
859981-.
|
Text
Homology Modeling, ide Novoi Design of Ligands, and Molecular Docking Identify Potential Inhibitors of iLeishmania donovanii.pdf - Published version Download (3MB) | Preview |
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. <i>Leishmania donovani</i> 24-sterol methyltransferase (<i>Ld</i>SMT) is vital for the synthesis of ergosterols, the main constituents of <i>Leishmania</i> 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 <i>Ld</i>SMT was elucidated using homology modeling to identify potential novel 24-SMT inhibitors <i>via</i> virtual screening, scaffold hopping, and <i>de-novo</i> 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 <b>S1</b>-<b>S4</b> obtained from scaffold hopping <i>via</i> 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 <i>Ld</i>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 <i>via</i> molecular dynamics simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) calculations. The ligand <b>A1</b> 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 <b>A5</b> and <b>A6</b> 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 <i>via</i> DrugBank identified vabicaserin, daledalin, zanapezil, imipramine, and cefradine with antileishmanial properties suggesting that the <i>de-novo</i> compounds could be explored as potential antileishmanial agents.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | leishmaniasis, 24-sterol methyltransferase, Leishmania donovani, de-novo drug design, molecular docking, molecular dynamics simulation |
| Divisions: | Faculty of Science and Engineering > School of Physical Sciences |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 22 Jul 2022 14:40 |
| Last Modified: | 16 Oct 2023 22:47 |
| DOI: | 10.3389/fcimb.2022.859981 |
| Open Access URL: | https://www.frontiersin.org/articles/10.3389/fcimb... |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3159188 |
Dimensions
Dimensions
