Targeting sterol alpha‐14 demethylase of Leishmania donovani to fight against leishmaniasis

Abstract

Leishmaniasis is a neglected tropical disease caused by the protozoan parasite Leishmania. It is endemic in more than 89 different countries worldwide. Sterol alpha‐14 demethylase (LdSDM), a sterol biosynthetic pathway enzyme in Leishmania donovani, plays an essential role in parasite survival and proliferation. Here, we used a drug repurposing approach to virtually screen the library of the Food and Drug Administration (FDA)‐approved drugs against LdSDM to identify the potential lead‐drug against leishmaniasis. Zafirlukast and avodart showed the best binding with LdSDM. Zafirlukast was tested for in vitro antileishmanial assay, but no significant effect on L. donovani promastigotes was observed even at higher concentrations. On the other hand, avodart profoundly inhibited parasite growth at relatively lower concentrations. Further, avodart showed a significant decrease in the number of intra‐macrophagic amastigotes. Avodart‐induced reactive oxygen species (ROS) in the parasites in a dose‐dependent manner. ROS induced by avodart led to the induction of apoptosis‐like cell death in the parasites as observed through annexin V/PI staining. Here, for the first time, we reported the antileishmanial activity and its possible mechanism of action of FDA‐approved drug, avodart, establishing a nice example of the drug‐repurposing approach. Our study suggested the possible use of avodart as an effective antileishmanial agent after further detailed validations.

Virtual screening of natural compounds for potential inhibitors of Sterol C‐24 methyltransferase of Leishmania donovani to overcome leishmaniasis

“…For the proliferation and viability within the macrophages, Leishmania sequesters cholesterol from the cholesterol biosynthetic pathway of the host 18,20 . Ergosterol is an important sterol, a by‐product of the vital sterol biosynthetic pathway 21 . It is present in the parasite cell membrane that regulates the membrane organization and fluidity 22 .…”

Novel chemical scaffold as potential drug against Leishmania donovani: Integrated computational and experimental approaches

“…Bazedoxifene is also good. Generally, lead compounds that had selectivity index values higher than 10 were regarded as promising 35 …”

“…The SI of all three compounds was found to be more compared with the SI of the Miltefosine in the case of promastigote, but in the case of intramacrophagic amastigote, only the compound Abemaciclib and Vorapaxar showed more SI value than Miltefosine. Overall, All compounds except Amyral and Imatinib demonstrated good antileishmanial activities with less cytotoxicity to mammalian cells as their selectivity index in the case of both promastigote and amastigote was found to be more than 10 35 . But among them, Abemaciclib showed the highest difference in free binding energy, 4.92 kcal/mol, with a free binding energy of human citrate synthase in molecular docking and also showed −203.47 ± 137.75 kJ/mol free binding energy in MMPBSA assay after MD simulation which indicates that this compound had a stable and strong binding affinity with the active site of citrate synthase.…”

Metabolic Pathways of Leishmania Parasite: Source of Pertinent Drug Targets and Potent Drug Candidates

“…These pathways and enzymes are precisely targeted via drug repurposing to treat leishmanial infection (Table 1) [18]. Studies reported that targeting enzymes involved in leishmanial sterol biosynthesis could significantly decrease parasite survival in the host [16], [22], [153]. Anti-malarial drugs like Spiro-indolone and spiro oxiindoles (JS87) target the enzyme SEs [22].…”

“…Recently, an electronic assessment of the FDA-approved drug library against L. donovani sterol alpha-14 demethylase using a drug repurposing approach suggested that Avodart significantly reduced the number of intra-macrophagic amastigotes. Avodart-induced ROS caused apoptosislike cell death in the parasites, which was identified by annexin V/PI staining [25].…”