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

2016 ◽  
Vol 165 ◽  
pp. 155-160 ◽  
Author(s):  
Xinya Han ◽  
Yunyuan Huang ◽  
Rui Zhang ◽  
San Xiao ◽  
Shuaihuan Zhu ◽  
...  
Keyword(s):  
Human Liver ◽  
Binding Modes ◽  
Fructose 1,6 Bisphosphatase ◽  
Insight Into

scholarly journals Characterization of the human liver fructose-1,6-bisphosphatase gene promoter

2000 ◽  
Vol 351 (2) ◽  
pp. 385 ◽  
Author(s):  
Birger HERZOG ◽  
Mary WALTNER-LAW ◽  
Donald K. SCOTT ◽  
Klaus ESCHRICH ◽  
Daryl K. GRANNER
Keyword(s):  
Human Liver ◽  
Gene Promoter ◽  
Fructose 1,6 Bisphosphatase

scholarly journals Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 61 ◽  
Author(s):  
Fernando Prieto-Martínez ◽  
José Medina-Franco
Keyword(s):  
Kinase Inhibitors ◽  
Binding Mode ◽  
Binding Modes ◽  
Ligand Interaction ◽  
Bet Inhibitors ◽  
Protein Ligand Interaction ◽  
Brd4 Inhibition ◽  
Dynamics Simulations ◽  
Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

Different Sensitivities of Mutants and Chimeric Forms of Human Muscle and Liver Fructose- 1,6-Bisphosphatases towards AMP

2003 ◽  
Vol 384 (1) ◽  
pp. 51-58 ◽  
Author(s):  
D. Rakus ◽  
H. Tillmann ◽  
R. Wysocki ◽  
S. Ulaszewski ◽  
K. Eschrich ◽  
...  
Keyword(s):  
Liver Enzyme ◽  
Human Liver ◽  
Human Muscle ◽  
Wild Type ◽  
Muscle Enzyme ◽  
Double Mutation ◽  
Binding Domains ◽  
Fructose 1,6 Bisphosphatase ◽  
Amp Inhibition ◽  
Acid Exchange

Abstract AMP is an allosteric inhibitor of human muscle and liver fructose-1,6-bisphosphatase (FBPase). Despite strong similarity of the nucleotide binding domains, the muscle enzyme is inhibited by AMP approximately 35 times stronger than liver FBPase: I0.5 for muscle and for liver FBPase are 0.14 uM and 4.8 uM, respectively. Chimeric human muscle (L50M288) and chimeric human liver enzymes (M50L288), in which the N-terminal residues (1-50) were derived from the human liver and human muscle FBPases, respectively, were inhibited by AMP 2-3 times stronger than the wild-type liver enzyme. An amino acid exchange within the Nterminal region of the muscle enzyme towards liver FBPase (Lys20→Glu) resulted in 13-fold increased I0.5 values compared to the wild-type muscle enzyme. However, the opposite exchanges in the liver enzyme (Glu20→Lys and double mutation Glu19→Asp/Glu20→Lys) did not change the sensitivity for AMP inhibition of the liver mutant (I0.5 value of 4.9 uM). The decrease of sensitivity for AMP of the muscle mutant Lys20→Glu, as well as the lack of changes in the inhibition by AMP of liver mutants Glu20→Lys and Glu19→Asp/Glu20→Lys, suggest a different mechanism of AMP binding to the muscle and liver enzyme.

scholarly journals Molecular Insight into the Synergism between the Minor Allele of Human Liver Peroxisomal Alanine:Glyoxylate Aminotransferase and the F152I Mutation

2009 ◽  
Vol 284 (13) ◽  
pp. 8349-8358 ◽  
Author(s):  
Barbara Cellini ◽  
Riccardo Montioli ◽  
Alessandro Paiardini ◽  
Antonio Lorenzetto ◽  
Carla Borri Voltattorni
Keyword(s):  
Human Liver ◽  
Minor Allele ◽  
Alanine:Glyoxylate Aminotransferase ◽  
Insight Into

scholarly journals Insight into the Binding and Hydrolytic Preferences of hNudt16 Based on Nucleotide Diphosphate Substrates

2021 ◽  
Vol 22 (20) ◽  
pp. 10929
Author(s):  
Magdalena Chrabąszczewska ◽  
Maria Winiewska-Szajewska ◽  
Natalia Ostrowska ◽  
Elżbieta Bojarska ◽  
Janusz Stępiński ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Substrate Specificity ◽  
Ligand Binding ◽  
Regulatory Role ◽  
Stacking Interactions ◽  
Binding Modes ◽  
Biological Functions ◽  
Insight Into ◽  
Potential Regulatory Role

Nudt16 is a member of the NUDIX family of hydrolases that show specificity towards substrates consisting of a nucleoside diphosphate linked to another moiety X. Several substrates for hNudt16 and various possible biological functions have been reported. However, some of these reports contradict each other and studies comparing the substrate specificity of the hNudt16 protein are limited. Therefore, we quantitatively compared the affinity of hNudt16 towards a set of previously published substrates, as well as identified novel potential substrates. Here, we show that hNudt16 has the highest affinity towards IDP and GppG, with Kd below 100 nM. Other tested ligands exhibited a weaker affinity of several orders of magnitude. Among the investigated compounds, only IDP, GppG, m7GppG, AppA, dpCoA, and NADH were hydrolyzed by hNudt16 with a strong substrate preference for inosine or guanosine containing compounds. A new identified substrate for hNudt16, GppG, which binds the enzyme with an affinity comparable to that of IDP, suggests another potential regulatory role of this protein. Molecular docking of hNudt16-ligand binding inside the hNudt16 pocket revealed two binding modes for representative substrates. Nucleobase stabilization by Π stacking interactions with His24 has been associated with strong binding of hNudt16 substrates.

Advances in Theoretical Studies on the Design of Single Boron Atom Compounds

2018 ◽  
Vol 24 (29) ◽  
pp. 3466-3475 ◽  
Author(s):  
Martiniano Bello
Keyword(s):  
Molecular Recognition ◽  
Drug Design ◽  
Boron Atom ◽  
Force Fields ◽  
Covalent Binding ◽  
Binding Modes ◽  
In Silico Studies ◽  
Reversible Covalent ◽  
The Individual ◽  
Insight Into

Background: Single Boron Atom Compounds (SBACs) have been used for drug discovery in diseaseassociated proteins due to the empty p-orbital in the atomic structure of boron, which allows it to experience diverse binding modes during molecular recognition with a range of proteins. Objective: During the molecular recognition process with a protein target, SBACs can assume an anionic tetragonal arrangement or a neutral trigonal planar structure to produce four possible reversible covalent or non-covalent binding modes with a protein. However, the development of new SBACs has been hampered by the fact that most of the force fields present in many of the software packages used in drug design lack the various types of boron atom parameters. Methods: We review in silico studies in which a series of theory-based computational strategies have been used to overcome the lack of boron parameters in most of the force fields used in drug design. Results: The modeling studies discussed in this review have provided substantial insight into the molecular recognition of SBACs targeting different receptors, including the elucidation of some of the key interactions, which serve as a guide for the development of selective SBACs. Conclusion: Although the strategies employed in many of the studies presented here should serve in the development of selective SBACs, it is clear that the development of the precise force field parameters, which include not only the individual atom types but also the entire molecule, is still lacking, yet it is a necessary requirement for the design of new SBACS as well as for gaining insight into their molecular recognition.

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