Modeled structure of trypanothione reductase of Leishmania infantum

Singh, B.K.; Sarkar, Nandini; Jagannadham, Medicherla V.; Dubey, Vikash Kumar

doi:10.5483/bmbrep.2008.41.6.444

Cited by 35 publications

(17 citation statements)

References 16 publications

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“…An anticarcinogen, 3,3′-diindolylmethane which is derived from indole-3-carbinol found in Brassica vegetables is found to have antileishmaniasis activity by inhibition of F 0 F 1 -ATP synthase [40]. Recently, our group has focused the attention on development of novel therapeutics against leishmaniasis by targeting parasitespecific trypanothione metabolic pathway [41,42].…”

Section: Resultsmentioning

confidence: 99%

Rational Approaches for Drug Designing Against Leishmaniasis

Shukla

Singh

Patra

et al. 2009

Appl Biochem Biotechnol

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Leishmaniasis has been ignored for many years mainly because it plagues remote and poor areas. However, recently, it has drawn attention of several investigators, and active research is going on for antileishmanial drug discovery. The current available drugs have high failure rates and significant side effects. Recently, liposomal preparations of amphotericin B are available and have proved to be a better drug, but they are very expensive. Miltefosine is one of the few orally administered drugs that are effective against Leishmania. However, it has exhibited teratogenicity, hence, should not be administered to pregnant women. Thus, the search for novel and improved antileishmanial drugs continue. A rational approach to design and develop new antileishmanials can be to identify several metabolic and biochemical differences between host and parasite that can be exploited as drug target. Moreover, many natural products also have significant antileishmanial activity and are yet to be exploited. In the current review, we aim to bring together various drug targets of Leishmania, recent development in the field, future prospects, and hope in the area.

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Section: Resultsmentioning

confidence: 99%

Rational Approaches for Drug Designing Against Leishmaniasis

Shukla

Singh

Patra

et al. 2009

Appl Biochem Biotechnol

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“…1) show significant similarity. 15,19 However, the overall sequence similarity of the two proteins is only 66.37% and residues making the environment of active site are different (Fig. 1), additionally similar residues have different rotamar angles.…”

Section: Introductionmentioning

confidence: 99%

Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum

2010

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Visceral leishmaniasis, most lethal form of Leishmaniasis, is caused by Leishmania infantum in the Old world. Current therapeutics for the disease is associated with a risk of high toxicity and development of drug resistant strains. Thiol-redox metabolism involving trypanothione and trypanothione reductase, key for survival of Leishmania, is a validated target for rational drug design. Recently published structure of trypanothione reductase (TryR) from L. infantum, in oxidized and reduced form along with Sb(III), provides vital clues on active site of the enzyme. In continuation with our attempts to identify potent inhibitors of TryR, we have modeled binding modes of selected tricyclic compounds and quinone derivatives, using AutoDock4. Here, we report a unique binding mode for quinone derivatives and 9-aminoacridine derivatives, at the FAD binding domain. A conserved hydrogen bonding pattern was observed in all these compounds with residues Thr335, Lys60, His461. With the fact that these residues aid in the orientation of FAD towards the active site forming the core of the FAD binding domain, designing selective and potent compounds that could replace FAD in vivo during the synthesis of Trypanothione reductase can be deployed as an effective strategy in designing new drugs towards Leishmaniasis. We also report the binding of Phenothiazine and 9-aminoacridine derivatives at the Z site of the protein. The biological significance and possible mode of inhibition by quinone derivatives, which binds to FAD binding domain, along with other compounds are discussed.

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“…The overall PROCHECK Gfactor for the homology modeled structure was -0.07 (Table 1). PROCHECK commonly used for structure validation (Singh and Dubey, 2009;Singh et al, 2008a and2008b). The model was also validated using ERRAT graph (Fig.…”

Section: Protein Structure Validationmentioning

confidence: 99%

In silico prediction and characterization of 3D structure and binding properties of catalase from the commercially important crab, Scylla serrata

Paital

Kumar

Farmer

et al. 2011

Interdiscip Sci Comput Life Sci

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The enzyme catalase breaks down H(2)O(2), a potentially harmful oxidant, to H(2)O and O(2). Besides oxidase activity, the enzyme also exhibits peroxidase activity. Therefore, it plays an important role in maintaining health and regulating pathophysiology of the organisms. However, 3D structure of this important enzyme in invertebrates particularly in crabs is not yet available. Therefore, an attempt has been made to predict the structure of the crab catalase and to envisage its catalytic interaction with H(2)O(2). A three dimensional model of crab catalase was constructed using the NADPH binding site on Beef Liver catalase from Bos taurus (PDBID: 7CAT) as template by comparative modeling approach. Backbone conformation of the modeled structure by PROCHECK revealed that more than 98% of the residues fell in the allowed regions, ERRAT results confirmed good quality of modeled structure and VERIFY3D profile was satisfying. Molecular docking has been used to know the binding modes of hydrogen peroxide with the crab catalase protein. The receptor structures used for docking were derived from molecular dynamics (MD) simulations of homology modeled structure. The docking results showed that the three important determinant residues Arg68, Val70 and Arg108 in catalase were binding with H(2)O(2) as they had strong hydrogen bonding contacts with the substrate. Our analysis provides insight into the structural properties of crab catalase and defines its active sites for binding with substrate. These data are important for further studies of catalase of invertebrates in general and that of crabs in particular.

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Modeled structure of trypanothione reductase of Leishmania infantum

Cited by 35 publications

References 16 publications

Rational Approaches for Drug Designing Against Leishmaniasis

Rational Approaches for Drug Designing Against Leishmaniasis

Molecular docking studies of selected tricyclic and quinone derivatives on trypanothione reductase of Leishmania infantum

In silico prediction and characterization of 3D structure and binding properties of catalase from the commercially important crab, Scylla serrata

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