Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani

Hazra, Somnath; Ghosh, Somsubhra; Sarma, Madhushree Das; Sharma, Smriti; Das, Mousumi; Saudagar, Prakash; Prajapati, Vijay Kumar; Dubey, Vikash Kumar; Sundar, Shyam; Hazra, Banasri

doi:10.1016/j.exppara.2013.07.021

Cited by 36 publications

(21 citation statements)

References 26 publications

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“…This drug has shown minimal side effect with antileishmanial activity in animal model, when it was administered orally (Wyllie, Patterson, & Fairlamb, 2013;Wyllie et al, 2012). interactions (Hazra et al, 2013;Verma et al, 2012) (Sahoo et al, 2014).…”

Section: Discussionmentioning

confidence: 97%

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

Pandey

Sharma

Bhatt

et al. 2015

Journal of Biomolecular Structure and Dynamics

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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.

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Section: Discussionmentioning

confidence: 97%

“…Molecular docking approach assist the protein interactions with ligand, other proteins, or surfaces and these are controlled by a complex array of intermolecular interactions (Hazra et al, 2013;Verma et al, 2012). The final goal of molecular docking is to predict the biological activity of given ligand.…”

Section: Introductionmentioning

confidence: 99%

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

Pandey

Sharma

Bhatt

et al. 2015

Journal of Biomolecular Structure and Dynamics

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“…Some other inhibitors of LdODC have shown antileishmanial effects (13). Our earlier studies indicate that diepoxide derivative of diospyrin acts as inhibitor of LdODC with antileishmanial activity (13). Further, we have reported modeled structure of LdODC and identified in silico inhibitors (14).…”

Section: Abstract: Inhibitors Leishmaniasis Ornithine Decarboxylasmentioning

confidence: 94%

“…DFMOresistant strain of Leishmania survives in the presence of DFMO, by a complex and partially deciphered mechanism involving many proteins (11,12). Some other inhibitors of LdODC have shown antileishmanial effects (13). Our earlier studies indicate that diepoxide derivative of diospyrin acts as inhibitor of LdODC with antileishmanial activity (13).…”

Section: Abstract: Inhibitors Leishmaniasis Ornithine Decarboxylasmentioning

confidence: 96%

Novel Inhibitors of Ornithine Decarboxylase of Leishmania Parasite (LdODC): The Parasite Resists LdODC Inhibition by Overexpression of Spermidine Synthase

2015

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Ornithine decarboxylase (LdODC), a key enzyme in polyamine biosynthesis in Leishmania donovani, catalyzes the conversion of ornithine to putrescine that is finally used for synthesis of spermidine and other polyamines. Inhibition of ornithine decarboxylase is likely to deplete the parasite trypanothione and may result in increased reactive oxygen species (ROS). Sequence as well as structure of LdODC and human ODC shows significant difference; therefore, we have identified novel specific inhibitors of LdODC. These inhibitors are able to inhibit recombinant LdODC and decrease intracellular putrescine concentration showing target specificity. The Ki values of LdODC inhibition do not correlate with IC50 values in Leishmania promastigote possibly due to different stability/pharmacokinetics. These inhibitors, except compound M-5, have only minor effect on Leishmania promastigotes, and IC50 values are several folds higher as compared to Ki values. In case of compound M-5, IC50 value is less than Ki value indicating that the compound may have additional targets. Our studies suggest that the parasite resists these LdODC inhibitors by overexpression of spermidine synthase mRNA.

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“…In another in vitro study both naphthoquinones 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (TR 001) and 2,3-dibromo-1,4-naphthoquinone (TR 002) also showed antileismanial activity 97 . Treatment of infected BALB/c mice with D17 a di-epoxide derivative of diospyrin (bis- naphthoquinone ) at 2mg/kg/day reduced the hepatic parasite load only by 38% 98 .…”

Section: Investigational Drugsmentioning

confidence: 99%

Investigational drugs for visceral leishmaniasis

Sundar

Chakravarty

2014

Expert Opinion on Investigational Drugs

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Introduction The armamentarium of antileishmanials is small. It is further being threatened by development of resistance and decreasing sensitivity to the available drugs. Development of newer drugs are sorely needed. Areas covered Literature search on investigational drugs for visceral leishmaniasis (VL) was done on PubMed. Those candidates with at least in vitro and in vivo activity against leishmania species causing VL were reviewed. Among the investigational drugs the nitroimidazole compound fexinidazole is the one of the few drugs which has reached phase II trials. Although the (S)-PA-824 is in phase II trials for the treatment of tuberculosis its R enantiomer has shown good antileishmanial activity. Development of sitamaquin, which has completed phase II studies has been stopped for VL due to its low efficacy. Many novel delivery system and oral formulations of Amphotericin B which are cheap and less toxic are in investigational stages, and will go a long way in improving the treatment of VL. Expert opinion Very few new drugs have reached the clinical stage in the treatment of this neglected tropical disease. Thus, there is an urgent need for support from public private partnerships to ensure that drug candidates are promptly taken forward into development.

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Evaluation of a diospyrin derivative as antileishmanial agent and potential modulator of ornithine decarboxylase of Leishmania donovani

Cited by 36 publications

References 26 publications

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

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

Novel Inhibitors of Ornithine Decarboxylase of Leishmania Parasite (LdODC): The Parasite Resists LdODC Inhibition by Overexpression of Spermidine Synthase

Investigational drugs for visceral leishmaniasis

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