Structural modeling and docking studies of ribose 5-phosphate isomerase from Leishmania major and Homo sapiens: A comparative analysis for Leishmaniasis treatment

Capriles, Priscila V. S. Z.; Baptista, Luiz Phillippe R.; Guedes, Isabella Alvim; Guimarães, Ana Carolina Ramos; Custódio, Fábio L.; Alves-Ferreira, Marcelo; Dardenne, Laurent E.

doi:10.1016/j.jmgm.2014.11.002

Cited by 23 publications

(21 citation statements)

References 46 publications

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“…It was interesting to note that Tyr46 which is found to be present in the substrate binding pocket of Ld RpiB and similarly reported for Tc RpiB and Lm RpiB, did not affect the kinetic parameters [ 9 , 11 ]. This mutant exhibited similar kinetic behaviour as the wild type and a structural conformation different from the wild type.…”

Section: Resultsmentioning

confidence: 70%

“…cruzi and the predicted residues of L . major [ 9 , 11 ]. Apart from these active site residues, three other conserved residues (Asp45, Pro47 and Glu149) were also evaluated for their role in structural integrity and catalytic function of Ld RpiB.…”

Section: Resultsmentioning

confidence: 99%

“…coli , Mycobacterium tuberculosis , Trypanosoma cruzi and L . major but interestingly the structures of RpiB from these organisms were very much similar [ 9 – 11 ]. It was proposed that isomerisation of R5P to Ru5P requires the open conformation of R5P (C-form).…”

Section: Introductionmentioning

confidence: 99%

“…The active site architecture of RpiA from Homo sapiens ( Hs RpiA) and RpiB from Leishmania major ( Lm RpiB) is highly different. Contrary to the Hs RpiA, Lm RpiB active site is characterized by the presence of many aromatic amino acid residues (His11, Tyr46, His102 and His138) apart from the negatively charged residue (Asp10 and Cys69) [ 9 ]. This significant difference in the catalytic site strengthens the possibility of designing parasite specific inhibitors without affecting the homologous human protein.…”

Section: Introductionmentioning

confidence: 99%

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Mutational and Structural Analysis of Conserved Residues in Ribose-5-Phosphate Isomerase B from Leishmania donovani: Role in Substrate Recognition and Conformational Stability

et al. 2016

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Ribose-5-phosphate isomerase B from Leishmania donovani (LdRpiB) is one of the potential drug targets against visceral leishmaniasis. In the present study, we have targeted several conserved amino acids for mutational analysis (i.e. Cys69, His11, His102, His138, Asp45, Tyr46, Pro47 and Glu149) to gain crucial insights into their role in substrate binding, catalysis and conformational stability of the enzyme. All the eight LdRpiB variants were cloned, sequenced, expressed and purified. C69S, H102N, D45N and E149A mutants exhibited complete loss of enzyme activity indicating that they are indispensable for the enzyme activity. Kinetic parameters were altered in case of H138N, H11N and P47A variants; however Y46F exhibited similar kinetic behaviour as wild type. All the mutants except H138N exhibited altered protein structure as determined by CD and fluorescence spectral analysis. This data was supported by the atomic level details of the conformational changes and substrate binding using molecular dynamic simulations. LdRpiB also exhibited activity with D-form of various aldose substrates in the order of D-ribose > D-talose > D-allose > D-arabinose. Our study provides insights for better understanding of substrate enzyme interactions which can rationalize the process of drug design against parasite RpiB.

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Section: Resultsmentioning

confidence: 70%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mutational and Structural Analysis of Conserved Residues in Ribose-5-Phosphate Isomerase B from Leishmania donovani: Role in Substrate Recognition and Conformational Stability

et al. 2016

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“…1,2 According to World Health Organization (WHO), around 1.3 million new cases occur per year. 3 Visceral leishmaniasis (VL) is the most severe form, in which vital organs are affected causing chronic fever, liver issues, spleen enlargement, anemia, and other blood problems.…”

mentioning

confidence: 99%

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

Gomes

Alcântara

Neves

et al. 2017

Bioorganic & Medicinal Chemistry Letters

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Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcones and chalcone-like compounds to act as anti-leishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2–10.98 μM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50 μM that resulted in better selectivity than Amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing of new anti-leishmanial chalcones.

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System Biology to Access Target Relevance in the Research and Development of Molecular Inhibitors

Catharina

Menezes

Carels

2018

Theoretical and Applied Aspects of Systems Biology

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Structural modeling and docking studies of ribose 5-phosphate isomerase from Leishmania major and Homo sapiens: A comparative analysis for Leishmaniasis treatment

Cited by 23 publications

References 46 publications

Mutational and Structural Analysis of Conserved Residues in Ribose-5-Phosphate Isomerase B from Leishmania donovani: Role in Substrate Recognition and Conformational Stability

Mutational and Structural Analysis of Conserved Residues in Ribose-5-Phosphate Isomerase B from Leishmania donovani: Role in Substrate Recognition and Conformational Stability

Computer-aided discovery of two novel chalcone-like compounds active and selective against Leishmania infantum

System Biology to Access Target Relevance in the Research and Development of Molecular Inhibitors

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