Binding of Fidarestat Stereoisomers with Aldose Reductase

Kim, Doo-Il; Hong, Seok-In; Lee, Dae-Sil

doi:10.3390/i7110519

Cited by 2 publications

(2 citation statements)

References 52 publications

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“…Such stereoisomers often differ in biological activities and pharmacokinetic profiles, and the use of such mixtures may result in adverse effects of the drug particularly if they are associated with the inactive or less active isomer (Hutt and O'Grady, 1996). Because the binding of a compound to a biomolecular receptor in the body is the first and critical step to initiate pharmacological effects (Lin et al, 2011), differential binding affinities of different stereoisomers with the target enzymes can lead to their different bioactivities (Kim et al, 2006). Chiral molecules will certainly play a role in the exploitation of three-dimensional space for the development of new drugs in the future.…”

Section: Introductionmentioning

confidence: 99%

Proteomic Comparison of the Cytotoxicology of Two Diastereomers of Citreamicin Reveals Differentially Activation of NF-κB Pathway

et al. 2020

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Citreamicin ε is a group of antitumor compounds produced by Streptomyces species. Cytotoxicology study of two diastereomers, citreamicin ε A and B, showed different apoptotic effects on PtK2 cells with IC 50 (half-maximal inhibitory concentration) values of 0.086 and 0.025 µM, respectively. Thus, we performed an iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomic analysis to reveal the mechanism of cytotoxicity of citreamicin ε A and B in PtK2 cells. A total of 1,079 proteins were identified and quantified, among which 103 and 94 proteins displayed significant changes in expression levels after the treatment of citreamicin ε A and B, respectively. These significantly differentially expressed proteins (DEPs) were further annotated by Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and proteinprotein interaction analysis, which revealed the involvement of eight molecular pathways. Among them, expression trends of proteins involved in the nuclear transcription factor κB (NF-κB) pathway displayed the opposite between the two diastereomer treatments, indicating different modes of action of these two compounds. Citreamicin ε A treatment induced rapid activation of the NF-κB pathway, which might promote cell survival and resulted in lower toxicity. Our comparative proteomic analysis provided molecular evidence on the toxicity of two diastereomers compounds to cells, which may shed new light on future mechanism study of these antitumor compounds.

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Section: Introductionmentioning

confidence: 99%

Proteomic Comparison of the Cytotoxicology of Two Diastereomers of Citreamicin Reveals Differentially Activation of NF-κB Pathway

et al. 2020

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“…The stereospecificity in binding to aldose reductase of fidarestat ((2R,4S) stereoisomer) compared to its (2R,4S) stereoisomer has been investigated by means of crystallographic structures analysis 67 and of molecular dynamics simulations using free energy integration techniques. 12 The two stereoisomers differ mainly in the orientation of the carbamoyl moiety with respect to the active site and rotation around the bond joining the carbamoyl substituent to the ring.…”

Section: Introductionmentioning

confidence: 99%

Charge Density and Electrostatic Interactions of Fidarestat, an Inhibitor of Human Aldose Reductase

et al. 2009

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The charge density and the topological features of fidarestat, an inhibitor of human aldose reductase, have been determined from ultra high-resolution X-ray diffraction data at 100 K. The modeled electron density was used to calculate the electrostatic interaction energy of fidarestat and its (2R,4S) stereoisomer with the human aldose reductase by using the ELMAM database as coded in the MoPro program. Such calculation may be extended to other protein complexes for which accurate high resolution X-ray data are available. The paper also discusses the hydrogen bonds in the fidarestat crystal. There are notably two hydrogen bonds with a pi system as an acceptor. All the chemical bonds and the intermolecular interactions, especially these two pi...H bonds, have been quantitatively studied by topological analysis. The three-dimensional electrostatic potential calculated on the molecular surface emphasizes the preferential polar binding sites of fidarestat. Theses interacting features in the molecule are crucial for drug-receptor recognition. The interactions between chemical groups in the crystal are also analyzed by computing the electrostatic energy using the latest advancements of the MoPro crystallographic software. The complexes of fidarestat and its (2R,4S) stereoisomer with human aldose reductase were modeled with a multipolar atom model transferred from our experimental electron density database. Accurate estimation of electrostatic interaction energy between inhibitors and the main residues of the protein active site is derived from this high detail level of the electron density.

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Binding of Fidarestat Stereoisomers with Aldose Reductase

Cited by 2 publications

References 52 publications

Proteomic Comparison of the Cytotoxicology of Two Diastereomers of Citreamicin Reveals Differentially Activation of NF-κB Pathway

Proteomic Comparison of the Cytotoxicology of Two Diastereomers of Citreamicin Reveals Differentially Activation of NF-κB Pathway

Charge Density and Electrostatic Interactions of Fidarestat, an Inhibitor of Human Aldose Reductase

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