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

Abstract

Leishmaniasis is a vector-borne disease caused by around 20 species of Leishmania.The main clinical forms of leishmaniasis are cutaneous leishmaniasis (CL) and visceral leishmaniasis (VL). VL is caused by Leishmania infantum in Central and South America, Mediterranean Basin, Middle East, and by L. donovani in Asia and Africa. Sterol C-24 methyltransferase (LdSMT) of L. donovani is a transferase enzyme of the sterol biosynthesis pathway. This pathway is one of the major targets for drug developments in Leishmania. Due to insufficient evidence about the exact function of SMT inside the cell and the uniqueness of the SMT enzyme in the Leishmania parasites made it a significant target for an effective drug development approach. We performed virtual screening of the Food and Drug Administration (FDA)-approved drug library against LdSMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with LdSMT. The binding was supported by hydrogen bonds and several other interactions. Simeprevir inhibited L. donovani growth of promastigotes with 50% inhibitory concentration (IC 50 ) of 51.49 ± 5.87 μM. Further studies showed that simeprevir induced ROS generation in 44.7% of parasites at 125-μM concentration. Here, we for the first time reported simeprevir as an antileishmanial lead molecule using a drug repurposing approach.

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

“…Though A1 , A2 , A3 , and A6 have similar core structures, they had different binding energies ( Table 2 ). Interestingly, using AutoDock Vina, compounds that had shown binding energies ≤−7.0 kcal/mol have been found to demonstrate significant inhibitory activities against the parasite of consideration ( Chang et al., 2007 ; Wyllie et al., 2018 ; Tabrez et al., 2021 ). In lieu of this, the predicted compounds may have the potential of suppressing Ld SMT since the binding energies were lower than −7.0 kcal/mol.…”

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

“…Molecular docking has been explored in the identification of lead compounds including gentisic acid 5-O glucoside [ 59 ], simeprevir [ 28 ], and bisindolylmaleimide IX [ 74 ] by targeting Buruli ulcer [ 59 ], visceral leishmaniasis [ 28 ], and SARS-CoV-2 [ 74 ], respectively. In all these instances, the binding energies associated with the protein–ligand complexes were used as part of the criteria to shortlist the hits.…”

“…To improve the inhibitory effect of 22,26-azsterol, some analogues ( Figure 1 ) were generated, and their activities were found to be dependent on the presence of ammonium or sulfonium functionality in the side chain [ 25 ]. 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 ].…”

Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review

“…Although medicine donation programs are multiplying to support the burden of neglected tropical diseases [150] such as leishmaniases, the pharmaceutical industry seems to increasingly restrict its research and development investment to new drug candidates [151]. Alternative options consist of repurposing drugs [152][153][154] or improving existing drugs, such as the gold standard amphotericin B [155]. Nevertheless, research into new drug candidates that are active against Leishmania must not be excluded, especially as methodological tools are becoming increasingly effective.…”