New insight into the binding modes of TNP-AMP to human liver fructose-1,6-bisphosphatase

Han, Xinya; Huang, Yunyuan; Zhang, Rui; Xiao, San; Zhu, Shuaihuan; Nian, Qin; Hong, Zongqin; Lin, Wenhan; Feng, Jiangtao; Ren, Yanliang; Feng, Lingling; Wan, Jian

doi:10.1016/j.saa.2016.04.002

Cited by 11 publications

(8 citation statements)

References 22 publications

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Section: Methodsmentioning

confidence: 99%

“…Full-length WT human liver FBPase (GenBank: D26055.1) was expressed in E. coli BL21 (DE3) and purified with a HisTrap_FF_5 mL [Global] column following the standard A ̈KTA pure system, and this process was performed as described in our previous work. 34 Enzymatic reactions were performed with purified enzyme (11.2 μg/mL) and FBP (0.4 mM/L) in 30 μL of buffer (50 mM/L Tris, 0.8 mM/L Mg 2+ ). After reacting for 5 min at 37 °C, 15 μL of 1 M perchloric acid was used to stop the reaction, and then malachite green (0.35% polyvinyl alcohol and 0.0035% malachite green) was added to quantify the inorganic phosphate.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

Huang

Song

et al. 2020

J. Med. Chem.

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Fructose 1,6-bisphosphatase (FBPase) has attracted substantial interest as a target associated with cancer and type 2 diabetes. Herein, we found that disulfiram and its derivatives can potently inhibit FBPase by covalently binding to a new C128 allosteric site distinct from the original C128 site in APO FBPase. Further identification of the allosteric inhibition mechanism reveals that the covalent binding of a fragment of 214 will result in the movement of C128 and the dissociation of helix H4 (123− 128), which in turn allows S123 to more easily form new hydrogen bonds with K71 and D74 in helix H3 (69−72), thereby inhibiting FBPase activity. Notably, both disulfiram and 212 might moderately reduce blood glucose output in vivo. Therefore, our current findings not only identify a new covalent allosteric site of FBPase but also establish a structural foundation and provide a promising way for the design of covalent allosteric drugs for glucose reduction.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

Huang

Song

et al. 2020

J. Med. Chem.

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“…Besides, a binding pocket was reported to be located at the interface of the two dimers. The AMP binding site has been explored more than the other two sites since it is easier to be bound by small ligands according to the previous reports [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Exploration of N-Arylsulfonyl-indole-2-carboxamide Derivatives as Novel Fructose-1,6-bisphosphatase Inhibitors by Molecular Simulation

Zhao

Yang

et al. 2022

IJMS

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A series of N-arylsulfonyl-indole-2-carboxamide derivatives have been identified as potent fructose-1,6-bisphosphatase (FBPase) inhibitors (FBPIs) with excellent selectivity for the potential therapy of type II diabetes mellitus. To explore the structure–activity relationships (SARs) and the mechanisms of action of these FBPIs, a systematic computational study was performed in the present study, including three-dimensional quantitative structure–activity relationship (3D-QSAR) modeling, pharmacophore modeling, molecular dynamics (MD), and virtual screening. The constructed 3D-QSAR models exhibited good predictive ability with reasonable parameters using comparative molecular field analysis (q2 = 0.709, R2 = 0.979, rpre2 = 0.932) and comparative molecular similarity indices analysis (q2 = 0.716, R2 = 0.978, rpre2 = 0.890). Twelve hit compounds were obtained by virtual screening using the best pharmacophore model in combination with molecular dockings. Three compounds with relatively higher docking scores and better ADME properties were then selected for further studies by docking and MD analyses. The docking results revealed that the amino acid residues Met18, Gly21, Gly26, Leu30, and Thr31 at the binding site were of great importance for the effective bindings of these FBPIs. The MD results indicated that the screened compounds VS01 and VS02 could bind with FBPase stably as its cognate ligand in dynamic conditions. This work identified several potential FBPIs by modeling studies and might provide important insights into developing novel FBPIs.

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“…Among several classes of known FBPase inhibitors, the phosphonic acid-containing thiazoles and AMP mimetic MB07803, a prodrug of MB07729, has advanced to a phase II clinical trial. ,, However, the development of competitive inhibitors is restricted due to several reasons, namely, the highly hydrophilic nature of the FBPase active site and the difficulty of designing suitable carbohydrate phosphate mimetics that can bind with higher affinity and compete with the high fructose 1,6-bisphosphate levels (resultant from FBPase inhibition). As such, a major effort has been focused on the design of AMP binding site inhibitors (noncompetitive inhibitors). ,,, …”

mentioning

confidence: 99%

“…As such, a major effort has been focused on the design of AMP binding site inhibitors (noncompetitive inhibitors). 1,2,11,15 Flavonoids, a class of phenolic secondary metabolites in plants with the basic structure of C 6 −C 3 −C 6 , are among the most wellstudied derived natural products, due to their recognized biological activities, including their potential antidiabetic activity. 16−25 However, there are few studies reported in the literature concerning the inhibitory activity of flavonoids against liver FBPase in diabetic rats or mice.…”

mentioning

confidence: 99%

Structural Specificity of Flavonoids in the Inhibition of Human Fructose 1,6-Bisphosphatase

et al. 2020

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Liver fructose 1,6-bisphosphatase (FBPase) is a recognized regulatory enzyme of the gluconeogenesis pathway, which has emerged as a valid target to control gluconeogenesis-mediated overproduction of glucose. As such, the management of diabetes with FBPase inhibitors represents a potential alternative for the currently used antidiabetic agents. In this study, the FBPase inhibition of a panel of 55 structurally related flavonoids was tested, through a microanalysis screening system. Then, a subset of seven active inhibitors and their close chemical relatives were further evaluated by molecular dynamics (MD) simulations using a linear interaction energy (LIE) approach. The results obtained showed that D14 (herbacetin) was the most potent inhibitor, suggesting that the presence of −OH groups at the C-3, C-4′, C-5, C-7, and C-8 positions, as well as the double bond between C-2 and C-3 and the 4-oxo function at the pyrone ring, are favorable for the intended effect. Furthermore, D14 (herbacetin) is stabilized by a strong interaction with the Glu30 side chain and the Thr24 backbone of FBPase. This is the first investigation studying the in vitro inhibitory effect of a panel of flavonoids against human liver FBPase, thus representing a potentially important step for the search and design of novel inhibitors of this enzyme.

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New insight into the binding modes of TNP-AMP to human liver fructose-1,6-bisphosphatase

Cited by 11 publications

References 22 publications

Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

Identification of the New Covalent Allosteric Binding Site of Fructose-1,6-bisphosphatase with Disulfiram Derivatives toward Glucose Reduction

Exploration of N-Arylsulfonyl-indole-2-carboxamide Derivatives as Novel Fructose-1,6-bisphosphatase Inhibitors by Molecular Simulation

Structural Specificity of Flavonoids in the Inhibition of Human Fructose 1,6-Bisphosphatase

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