Developing imidazole analogues as potential inhibitor forLeishmania donovanitrypanothione reductase: virtual screening, molecular docking, dynamics and ADMET approach

Abstract

Visceral leishmaniasis (VL) affects Indian subcontinent, African and South American continent, and it covers 70 countries worldwide. Visceral form of leishmaniasis is caused by Leishmania donovani in Indian subcontinent which is lethal if left untreated. Extensive resistance to antileishmanial drugs such as sodium stibogluconate, pentamidine and miltefosine and their decreased efficacy has been reported in the endemic region. Amphotericin B drug has shown good antileishmanial activity with significant toxicity, but its cost of treatment has limited the outreach of this treatment to affected people living in endemic zone. So, there is an urgent need to identify new antileishmanial drugs with excellent activity and minimal toxicity issues. Trypanothione reductase, a component of antioxidant system, is necessary for parasite growth and survival to raise infection. To develop potential inhibitor, we docked nine hundred and eighty-four 5-nitroimidazole analogues along with clomipramine which is a well-known inhibitor for TR. Total one hundred and forty-seven 5-nitroimidazole analogues with better docking score than clomipramine were chosen for ADMET and QikProp studies. Among these imidazole analogues, total twenty-four imidazole analogues and clomipramine were chosen on the basis of their ADMET, QikProp, and prime MM-GBSA study. Later on, two analogues with best MM-GBSA dG bind were undergone molecular dynamic simulation to ensure protein-ligand interactions. Using above approach, we confirm that ethyl 2-acetyl-5-[4-butyl-2-(3-hydroxypentyl)-5-nitro-1H-imidazol-1-yl]pent-2-enoate can be a drug candidate against L. donovani for the treatment of VL in the Indian subcontinent.

Novel Immunoinformatics Approaches to Design Multi-epitope Subunit Vaccine for Malaria by Investigating Anopheles Salivary Protein

“…Molecular docking of subunit vaccine protein and TLR-4 receptor was performed using the ClusPro 2.0 and total 30 models were generated 38 . Among them, only that model was selected which properly occupied the receptor and having lowest energy score and found that model number 0.00 fulfill the desired criteria that’s why selected as the best-docked complex (Fig.…”

High-throughput virtual screening and quantum mechanics approach to develop imipramine analogues as leads against trypanothione reductase of leishmania

“…Nanonization of amphotericin-B has also shown increased efficacy [24,25] and its carbon nanotube attached form made it suitable for targeted killing of leishmania parasite in both in vitro and in vivo experiments [26,27]. Recently, Pandey RK et al have reported imidazole and febrifugine analogues as an antileishmanial drug candidate against TR of L. donovani against their native use to treat human african trypanosomiasis and malaria respectively [4,28]. Compounds with imipramine nucleus have been reported against TR of Trypanosoma cruzi and showed strong inhibitory effect [12].…”

“…In the Indian subcontinent, some district of Bihar state has challenged worst endemic since 1970s [3]. Leishmania donovani is the major species to cause visceral leishmaniasis (VL) in the Indian subcontinent while Leishmania infantum grant for the same in the new world [4]. However, the life cycle of L. donovani is digenetic; the extracellular flagellated promastigotes form is present in sandflies while intracellular aflagellated amastigotes form is present in mononuclear phagocytes of mammalian host.…”

An immunoinformatics approach for the design of a multi-epitope subunit vaccine for urogenital schistosomiasis

“…A protein-protein docking analysis was carried out to determine the immune response of TLR-4 agonists against the multi-epitope subunit vaccine designed by minimizing the potential energy of the complete system. The energy minimization ensured conformational stability of designed vaccine-TLR-4 complex by repairing the unnecessary geometry of the structure (Pandey et al, 2017;Pandey et al, 2015). El-Din (2016) has reported decrease in S. mansoni worm load, egg load and granuloma size during TLR4 and TLR 9 stimulation with upregulated expression of macrophages.…”