Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket

Tso, Shih Chia; Qi, Xiangbing; Gui, Wenjun; Wu, Cheng-Yang; Chuang, Jacinta L.; Asterholm, Ingrid Wernstedt; Morlock, Lorraine; Owens, Kyle; Scherer, Philipp E.; Williams, Noelle S.; Tambar, Uttam K.; Wynn, R. Max; Chuang, David T.

doi:10.1074/jbc.m113.533885

Cited by 90 publications

(113 citation statements)

References 52 publications

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“…Negatively charged ASP 290 and GLU 262 present in the binding pocket were found to be interacting with the compound. Our results coincide with the active site interaction of (5-Bromo-2, 4-Dihydroxyphenyl)(1,3-Dihydro-2 h-Isoindol- 2-Yl) methanone with ATP binding pocket [18,28]. …”

Section: Resultssupporting

confidence: 86%

“…PDK plays a crucial role in glucose utilization and lipid metabolism through pyruvate dehydrogenase complex. In diabetes, PDK2 activity is markedly upregulated and PDK2 has been an emerging therapeutic target for type 2 diabetes as well as a candidate gene for that disease [18]. In our docking study of 4MP2 (Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1) with the novel compound revealed that ARG 258 forms the strong hydrogen bond interaction with C = O of the novel compound.…”

Section: Resultsmentioning

confidence: 97%

“…Pyruvate dehydrogenase kinase isoforms (PDKs 1 - 4) (PDB ID 4MP2) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure and cancer and are potential therapeutic targets for these important human diseases [18]. Glucokinase (hexokinase IV) has a major role in the control of blood glucose homeostasis because it is the predominant hexokinase expressed in the liver, has a very high control strength on hepatic glucose disposal, and is the glucose sensor for insulin secretion in pancreatic β-cells.…”

Section: Introductionmentioning

confidence: 99%

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Molecular docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone from Grewia hirsuta with some targets related to type 2 diabetes

Natarajan

Shobana

Sivakumar

et al. 2015

BMC Complement Altern Med

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BackgroundManagement of diabetes without any side effects is still a challenge to the medical system. This leads to increasing demand for natural products with antidiabetic activity with fewer side effects. Grewia hirsuta (Tiliaceae) is a traditional herbal medicinal plant and is reported to possess a variety of pharmacological actions. In the present research, a compound (4Z, 12Z)-cyclopentadeca-4, 12-dienone isolated from Grewia hirsuta was taken as ligand for molecular docking studies. Evaluation of hypoglycemic activity through an extensive in silico docking approach with molecular targets such as aldose reductase, glucokinase, pyruvate dehydrogenase kinase isoform 2, peroxisome proliferator-activated receptor-gamma, glycogen synthase kinase-3, 11β-Hydroxysteroid dehydrogenase, and glutamine: fructose-6-phosphate amidotransferase were performed.MethodsIsolation of the (4Z, 12Z)-cyclopentadeca-4,12-dienone from the methanol extract of the leaves of Grewia hirsuta was performed by the column chromatography to yield different fractions. These fractions were then subjected to purification and the structure was elucidated and confirmed by spectroscopic methods including UV, FTIR, 1H, 13C NMR and the accurate mass determination was carried out using the Q-TOF mass spectrometer. In-vivo experimentation was performed with evaluation of α-glucosidase, α-amylase and MTT assay that had been reported by the author in the earlier paper. Molecular docking study was performed with GLIDE docking software.ResultsThe docking studies of the ligand (4Z, 12Z)-cyclopentadeca-4, 12-dienone with seven different target proteins showed that this is a good inhibitor, which docks well with various targets related to diabetes mellitus. Hence (4Z, 12Z)-cyclopentadeca-4,12-dienone can be considered for developing into a potent anti-diabetic drug.ConclusionThe results of the current study have revealed that the leaves of the selected plant Grewia hirsuta contains a potential inhibitor for diabetes (4Z, 12Z)-cyclopentadeca-4,12-dienone. Thus enabling a possibility of this plant extract as a new alternative to existing diabetic approaches.

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Section: Resultssupporting

confidence: 86%

Section: Resultsmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Molecular docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone from Grewia hirsuta with some targets related to type 2 diabetes

Natarajan

Shobana

Sivakumar

et al. 2015

BMC Complement Altern Med

View full text Add to dashboard Cite

show abstract

“…Studies in somatic cells indicate that PDH activity is inhibited by site-specific phosphorylation at three serine residues of the E1 α subunit (PDHE1α): Ser232, Ser293 and Ser300 (Hitosugi et al, 2011;Korotchkina and Patel, 2001;Rardin et al, 2009). To date, four paralogous PDK genes (PDK1-PDK4) have been identified in mammals (Gudi et al, 1995;Tso et al, 2014). PDK1 expression is limited to heart and PDK3 is mainly found in testis, whereas PDK2 can be detected in many tissues.…”

Section: Introductionmentioning

confidence: 99%

Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation

Hou

Zhang

Han

et al. 2015

Journal of Cell Science

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Pyruvate dehydrogenase kinases (PDKs) modulate energy homeostasis in multiple tissues and cell types, under various nutrient conditions, through phosphorylation of the α subunit (PDHE1α, also known as PDHA1) of the pyruvate dehydrogenase (PDH) complex. However, the roles of PDKs in meiotic maturation are currently unknown. Here, by undertaking knockdown and overexpression analysis of PDK paralogs (PDK1-PDK4) in mouse oocytes, we established the site-specificity of PDKs towards the phosphorylation of three serine residues (Ser232, Ser293 and Ser300) on PDHE1α. We found that PDK3-mediated phosphorylation of Ser293-PDHE1α results in disruption of meiotic spindle morphology and chromosome alignment and decreased total ATP levels, probably through inhibition of PDH activity. Unexpectedly, we discovered that PDK1 and PDK2 promote meiotic maturation, as their knockdown disturbs the assembly of the meiotic apparatus, without significantly altering ATP content. Moreover, phosphorylation of Ser232-PDHE1α was demonstrated to mediate PDK1 and PDK2 action in meiotic maturation, possibly through a mechanism that is distinct from PDH inactivation. These findings reveal that there are divergent roles of PDKs during oocyte maturation and indicate a new mechanism controlling meiotic structure.

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“…Recombinant human pyruvate dehydrogenase kinase isoform 2 (PDK2) and its inhibitors (PS10 and PS8) were prepared as described [23]. …”

Section: Methodsmentioning

confidence: 99%

High-precision, automated integration of multiple isothermal titration calorimetric thermograms: New features of NITPIC

Scheuermann

Brautigam

2015

Methods

171

132

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Isothermal titration calorimetry (ITC) has become a standard and widely available tool to measure the thermodynamic parameters of macromolecular associations. Modern applications of the method, including global analysis and drug screening, require the acquisition of multiple sets of data; sometimes these data sets number in the hundreds. Therefore, there is a need for quick, precise, and automated means to process the data, particularly at the first step of data analysis, which is commonly the integration of the raw data to yield an interpretable isotherm. Herein, we describe enhancements to an algorithm that previously has been shown to provide an automated, unbiased, and high-precision means to integrate ITC data. These improvements allow for the speedy and precise serial integration of an unlimited number of ITC data sets, and they have been implemented in the freeware program NITPIC, version 1.1.0. We present a comprehensive comparison of the performance of this software against an older version of NITPIC and a current version of Origin, which is commonly used for integration. The new methods recapitulate the excellent performance of the previous versions of NITPIC while speeding it up substantially, and their precision is significantly better than that of Origin. This new version of NITPIC is therefore well suited to the serial integration of many ITC data sets.

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Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket

Cited by 90 publications

References 52 publications

Molecular docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone from Grewia hirsuta with some targets related to type 2 diabetes

Molecular docking studies of (4Z, 12Z)-cyclopentadeca-4, 12-dienone from Grewia hirsuta with some targets related to type 2 diabetes

Differing roles of pyruvate dehydrogenase kinases during mouse oocyte maturation

High-precision, automated integration of multiple isothermal titration calorimetric thermograms: New features of NITPIC

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