Design, synthesis, and evaluation of substrate – analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B

Gonzalez, Soledad Natalia; Mills, Jonathan J.; Maugeri, Dante; Olaya, Christopher; Laguera, Breana; Enders, Jeffrey R.; Sherman, Julian; Rodrı́guez, Ana; Pierce, Joshua G.; Cazzulo, Juán José; D'Antonio, E.L.

doi:10.1016/j.bmcl.2020.127723

Cited by 4 publications

(4 citation statements)

References 30 publications

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“…Since RPI-B is a competitor enzyme of RPE and also utilizes Ru5P as a substrate, molecular docking studies of LdRPE with these inhibitors revealed them to be fitting in the substrate-binding pocket with higher binding affinity than the substrate (Ru5P), advocating that the mode of inhibition is competitive. In corroboration with the previous in vitro study, 37 B displays a better binding affinity toward leishmanial RPE in comparison to the substrate. The stability, flexibility, and compactness of LdRPE in the presence of substrate analogues (Comp A−E) were found to be better than the apo as well as complexes with the substrate and product, which delineated a stable interaction of the respective compounds in the binding pocket.…”

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

“…Further analysis of molecular interactions of Ld RPE with the substrate and product revealed that it possesses a single binding pocket for the substrate and product, which was also reported in the crystal structure of its counterpart in human. 8 Recently, Gonzalez and co-workers 37 identified substrate (Ru5P)-analogue derivatives, compounds A–E and found that these compounds inhibit RPI-B of T. cruzi through a competitive mode of action. Since RPI-B is a competitor enzyme of RPE and also utilizes Ru5P as a substrate, molecular docking studies of Ld RPE with these inhibitors revealed them to be fitting in the substrate-binding pocket with higher binding affinity than the substrate (Ru5P), advocating that the mode of inhibition is competitive.…”

Section: Discussionmentioning

confidence: 99%

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Biophysical and Structural Characterization of Ribulose-5-phosphate Epimerase from Leishmania donovani

Narsimulu

Qureshi²,

Jakkula

et al. 2021

ACS Omega

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Pentose phosphate pathway (PPP) plays a crucial role in the maintenance of NADPH/NADP + homeostasis and provides protection against oxidative stress through detoxification of the reactive oxygen species. Ribulose-5-phosphate epimerase (RPE) participates in catalysis of the interconversion of ribulose-5-phosphate (Ru5P) to xylulose-5-phosphate (Xu5P) during PPP, however the structural attributes of this enzyme are still underexplored in many human pathogens including leishmanial parasites. The present study focuses upon cloning, purification and characterization of RPE of Leishmania donovani ( Ld RPE) using various biophysical and structural approaches. Sequence analysis has shown the presence of trypanosomatid-specific insertions at the N-terminus that are absent in humans and other eukaryotes. Gel filtration chromatography indicated recombinant Ld RPE to exist as a dimer in the solution. Circular dichroism studies revealed a higher alpha helical content at physiological pH and temperature that comparatively varies with changing these parameters. Additionally, intrinsic fluorescence and quenching studies of Ld RPE have depicted that tryptophan residues are mainly buried in the hydrophobic regions, and the recombinant enzyme is moderately tolerant to urea. Moreover, homology modeling was employed to generate the three-dimensional structure of Ld RPE followed by molecular docking with the substrate, product, and substrate analogues. The modeled structure of Ld RPE unravelled the presence of conserved active site residues as well as a single binding pocket for the substrate and product, while an in silico study suggested binding of substrate analogues into a similar pocket with more affinity than the substrate. Additionally, molecular dynamics simulation analysis has deciphered complexes of Ld RPE with most of the ligands exhibiting more stability than its apo form and lesser fluctuations in active site residues in the presence of ligands. Altogether, our study presents structural insights into leishmanial RPE that could provide the basis for its implication to develop potent antileishmanials.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

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Biophysical and Structural Characterization of Ribulose-5-phosphate Epimerase from Leishmania donovani

Narsimulu

Qureshi²,

Jakkula

et al. 2021

ACS Omega

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“…Likewise, ribose-5-phosphate isomerase (Rpi) has been suggested as a new drug target in T. cruzi , and molecules that may work as selective inhibitors were identified by virtual screening. 59 , 60 , 61 An investigation of the sequence diversity among TcRpi protein sequences available in public databases showed 36 distinct clusters among 277 T. cruzi genomes (Azevedo et al, unpublished observations). Although most of the 160 amino acids in TcRpi are conserved, some polymorphic positions were observed immediately adjacent to the catalytic residues suggesting functional impact and the need of further investigation with experimental and computational approaches to address this issue.…”

mentioning

confidence: 99%

Genomic surveillance: a potential shortcut for effective Chagas disease management

Azevedo

Catanho

Guimarães

et al. 2022

Mem. Inst. Oswaldo Cruz

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Chagas disease is an enduring public health issue in many Latin American countries, receiving insufficient investment in research and development. Strategies for disease control and management currently lack efficient pharmaceuticals, commercial diagnostic kits with improved sensitivity, and vaccines. Genetic heterogeneity of Trypanosoma cruzi is a key aspect for novel drug design since pharmacological technologies rely on the degree of conservation of parasite target proteins. Therefore, there is a need to expand the knowledge regarding parasite genetics which, if fulfilled, could leverage Chagas disease research and development, and improve disease control strategies. The growing capacity of whole-genome sequencing technology and its adoption as disease surveillance routine may be key for solving this long-lasting problem.

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At the outer part of the active site in Trypanosoma cruzi glucokinase: The role of phenylalanine 337

Carey,

Kearns,

Millington

et al. 2024

Biochimie

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Design, synthesis, and evaluation of substrate – analogue inhibitors of Trypanosoma cruzi ribose 5-phosphate isomerase type B

Cited by 4 publications

References 30 publications

Biophysical and Structural Characterization of Ribulose-5-phosphate Epimerase from Leishmania donovani

Biophysical and Structural Characterization of Ribulose-5-phosphate Epimerase from Leishmania donovani

Genomic surveillance: a potential shortcut for effective Chagas disease management

At the outer part of the active site in Trypanosoma cruzi glucokinase: The role of phenylalanine 337

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