Identification of potential inhibitors for Sterol C-24 reductase of Leishmania donovani through virtual screening of natural compounds
  • FAZLUR RAHMAN1,#, SHAMS TABREZ1,#, RAHAT ALI1, SAJJADUL KADIR AKAND1, MOHAMMED A. ALAIDAROUS2,3, MOHAMMED ALSAWEED2, BADER MOHAMMED ALSHEHRI2, SAEED BANAWAS2,3, ABDUR RUB1,*, ABDUL AZIZ BIN DUKHYIL2,*
1 Infection and Immunity Laboratory (414), Department of Biotechnology, Jamia Millia Islamia-A Central University, New Delhi, 110025, India
2 Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, 11952, Saudi Arabia
3 Health and Basic Sciences Research Center, Majmaah University, Al Majmaah, 11952, Saudi Arabia
* Address correspondence to: Abdur Rub, arub@jmi.ac.in; Abdul Aziz Bin Dukhyil, a.dukhyil@mu.edu.sa
# These authors contributed equally to this work
Received 17 March 2021; Accepted 25 April 2021 ; Published online 17 June 2021
Abstract
Leishmaniasis is a vector-borne parasitic neglected tropical disease caused by a group of about 30 different species of the genus Leishmania. It is transmitted by the bite of female phlebotomies sand fly. Three main clinical manifestations of leishmaniasis include cutaneous, visceral, and mucocutaneous leishmaniasis. Visceral leishmaniasis (VL) caused by Leishmania donovani, is an infection of reticuloendothelial system and fatal if untreated. Cholesterol, a sterol that is prominent in the mammalian cell membranes whereas stigmasterol and ergosterol are more prevalent in plants, yeast, and protozoa, respectively. Ergosterols which is absent in human being, is an important constituent of parasite membrane. Sterol C-24 reductase (LdSR) enzyme catalyzes the final step in the ergosterol biosynthesis pathway. The inhibition of biosynthesis of ergosterol may lead to decreased cell viability and growth. Here, we performed the molecular docking-based virtual screening of a library of natural ligands against LdSR to identify a potential inhibitor to fight leishmaniasis. Capsaicin, prenyletin, flavan-3-ol, resveratrol, and gingerol showed the top binding affinity towards LdSR. Based upon ADME properties and bioactivity score, gingerol showed the best lead-likeness and drug-likeness properties. Hence, we further annotated its leishmanicidal properties. We found that gingerol inhibited the growth and proliferation of promastigotes as well as intra-macrophagic amastigotes. Gingerol exerted its antileishmanial action through the induction of reactive oxygen species (ROS) in concentration-dependent manner. Gingerol induced ROS led to apoptosis. Overall, this study described that gingerol would act as possible inhibitor to LdSR.
Keywords
Leishmania, Gingerol, Sterol C-24 reductase, Molecular docking, ROS