Repurposing of <scp>FDA</scp>‐approved drugs as inhibitors of sterol C‐24 methyltransferase of <i>Leishmania donovani</i> to fight against leishmaniasis
Shams Tabrez, Fazlur Rahman, Rahat Ali, Fida Muhammad, Bader Alshehri, Mohammed Alaidarous, Saeed Banawas, Abdul Aziz Bin Dukhyil, Abdur Rub
Abstract
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 ( Ld SMT) 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 Ld SMT and found simeprevir, an antiviral drug on top in the binding score. It showed a significant binding affinity with Ld SMT. 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.