Glutamate Dehydrogenase as a Promising Target for Hyperinsulinism Hyperammonemia Syndrome Therapy.

2021 ◽  
Vol 28 ◽  
Author(s):  
Yunfei Bian ◽  
Wei Hou ◽  
Xinrou Chen ◽  
Jinzhang Fang ◽  
Ning Xu ◽  
...  
Keyword(s):  
Glutamate Dehydrogenase ◽  
Binding Sites ◽  
Screening Methods ◽  
Mitochondrial Matrix ◽  
Promising Target ◽  
Potential Binding ◽  
Permanent Brain Damage ◽  
Severe Epilepsy ◽  
Recurrent Hypoglycemia ◽  
Persistent Elevation

: Hyperinsulinism-hyperammonemia syndrome (HHS) is a rare disease characterized by recurrent hypoglycemia and persistent elevation of plasma ammonia, and it can lead to severe epilepsy and permanent brain damage. It has been demonstrated that functional mutations of glutamate dehydrogenase (GDH), an enzyme in the mitochondrial matrix, are responsible for the HHS. Thus, GDH has become a promising target for the small molecule therapeutic intervention of HHS. Several medicinal chemistry studies are currently aimed at GDH, however, to date, none of the compounds reported has been entered clinical trials. This perspective summarizes the progress in the discovery and development of GDH inhibitors, including the pathogenesis of HHS, potential binding sites, screening methods, and research models. Future therapeutic perspectives are offered to provide a reference for discovering potent GDH modulators and encourage additional research that will provide more comprehensive guidance for drug development.

scholarly journals Druggable Transient Pockets in Protein Kinases

Molecules ◽  
2021 ◽  
Vol 26 (3) ◽  
pp. 651
Author(s):  
Koji Umezawa ◽  
Isao Kii
Keyword(s):  
Drug Discovery ◽  
Small Molecules ◽  
Protein Kinases ◽  
Binding Sites ◽  
Kinase Inhibitors ◽  
Screening Methods ◽  
Research Attention ◽  
Folding Process ◽  
Chemical Screening ◽  
Inhibitory Mechanisms

Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of “cryptic inhibitor-binding sites.” These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.

scholarly journals Connecting Structure with Kinetics of Single-Stranded DNA Fluctuations that Provide Potential Binding Sites for Replication Proteins

2021 ◽  
Vol 120 (3) ◽  
pp. 219a
Author(s):  
Claire Albrecht ◽  
Brett A. Israels ◽  
Chloe Chvatal ◽  
Peter H. von Hippel ◽  
Andrew H. Marcus
Keyword(s):  
Binding Sites ◽  
Replication Proteins ◽  
Single Stranded Dna ◽  
Potential Binding ◽  
Kinetics Of

scholarly journals An In-Silico Study of Stable and Environment-Friendly Oryza sativa Urease

2020 ◽  
Vol 11 (3) ◽  
pp. 10238-10247
Keyword(s):  
Oryza Sativa ◽  
Binding Sites ◽  
3D Structure ◽  
Crop Productivity ◽  
Environment Friendly ◽  
Potential Binding ◽  
Urease Enzyme ◽  
In Silico Study ◽  
Stable Mutant ◽  
Detrimental Impact

Urea is one of the most extensively used fertilizers in agriculture but has a detrimental impact on the environment. One of the strategies to reduce this impact can be engineering modified plants containing urease enzyme with a considerably higher affinity for urea so that the urea applied in the fields can be significantly reduced. In this study, we have selected Oryza sativa Urease and generated stable mutants having a high affinity for urea. We modeled the 3D structure of the enzyme and identified the potential binding sites by analyzing the binding sites of similar proteins, i.e., 48 urea binding proteins. We found that mutation of Arg578 with Cys near the substrate-binding site of Oryza sativa Urease leads to a stable mutant protein that has a higher binding affinity for urea. This study will lead to a generation of environment-friendly, stable, genetically modified rice crop that consumes lesser urea, without compromising with crop productivity.

scholarly journals INSILICO STUDIES OF OXIME PRODRUG OF GLICLAZIDE AGAINST SULPHONYLUREA RECEPTORS (SUR 1)

2017 ◽  
Vol 9 (4) ◽  
pp. 100
Author(s):  
Surendran Vijayaraj ◽  
Kannekanti Chaithanya Veena
Keyword(s):  
Binding Sites ◽  
Pancreatic Beta Cells ◽  
Molecular Targets ◽  
Docking Studies ◽  
Docking Analysis ◽  
Potential Binding ◽  
In Silico Study ◽  
Molecular Docking Analysis ◽  
Autodock 4.2

Objective: Objective of the study is to perform a molecular docking analysis of novel oxime prodrug of gliclazide against SUR1 receptor.Methods: Sulfonylurea receptors (SUR) are membrane proteins which are the molecular targets of the sulfonylurea class of anti-diabetic drugs whose mechanism of action is to promote insulin release from pancreatic beta cells. Oxime prodrug of gliclazide a better soluble derivative of gliclazide is used for enhancement of bioavailability of gliclazide. Autodock 4.2 software was used for docking studies. Ligand 2D structures were drawn using ChemDraw Ultra 7.0. Binding sites, docking poses and interactions of the ligand with SUR1 receptors were studied by pymol software.Results: The docking studies suggest that potential binding sites of oxime prodrug of gliclazide exhibiting all the major interactions such as hydrogen bonding, hydrophobic interaction and electrostatic interaction with GLU43, LEU11, LEU 40, ILE17 GLU 68, GLN72 residues of SUR1. The binding energy of complexes are also found to be minimal forming stable complexes.Conclusion: In silico study of oxime prodrug of gliclazide conforms, the binding of oxime prodrug of glicalzide with SUR1 receptors which effectively controls the release insulin to regulate plasma glucose concentrations. Hence, the oxime prodrug of gliclazide could be a potent anti-diabetic target molecule which may be worth for further in vitro and in vivostudies. 

scholarly journals The Retinoid and Non-Retinoid Ligands of the Rod Visual G Protein-Coupled Receptor

2019 ◽  
Vol 20 (24) ◽  
pp. 6218 ◽  
Author(s):  
Joseph T. Ortega ◽  
Beata Jastrzebska
Keyword(s):  
Drug Discovery ◽  
G Protein ◽  
Binding Sites ◽  
Binding Pocket ◽  
Biologically Active ◽  
Surface Receptors ◽  
Beneficial Effects ◽  
Light Sensing ◽  
Potential Binding ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) play a predominant role in the drug discovery effort. These cell surface receptors are activated by a variety of specific ligands that bind to the orthosteric binding pocket located in the extracellular part of the receptor. In addition, the potential binding sites located on the surface of the receptor enable their allosteric modulation with critical consequences for their function and pharmacology. For decades, drug discovery focused on targeting the GPCR orthosteric binding sites. However, finding that GPCRs can be modulated allosterically opened a new venue for developing novel pharmacological modulators with higher specificity. Alternatively, focus on discovering of non-retinoid small molecules beneficial in retinopathies associated with mutations in rhodopsin is currently a fast-growing pharmacological field. In this review, we summarize the accumulated knowledge on retinoid ligands and non-retinoid modulators of the light-sensing GPCR, rhodopsin and their potential in combating the specific vision-related pathologies. Also, recent findings reporting the potential of biologically active compounds derived from natural products as potent rod opsin modulators with beneficial effects against degenerative diseases related to this receptor are highlighted here.

scholarly journals DNA Binding Site Selection of Dimeric and Tetrameric Stat5 Proteins Reveals a Large Repertoire of Divergent Tetrameric Stat5a Binding Sites

2000 ◽  
Vol 20 (1) ◽  
pp. 389-401 ◽  
Author(s):  
Elisabetta Soldaini ◽  
Susan John ◽  
Stefano Moro ◽  
Julie Bollenbacher ◽  
Ulrike Schindler ◽  
...  
Keyword(s):  
Binding Site ◽  
Dna Sequences ◽  
Site Selection ◽  
Binding Sites ◽  
Tetramer Binding ◽  
Dna Binding Site ◽  
Potential Binding ◽  
Wide Range ◽  
Large Repertoire ◽  
Selection Of

ABSTRACT We have defined the optimal binding sites for Stat5a and Stat5b homodimers and found that they share similar core TTC(T/C)N(G/A)GAA interferon gamma-activated sequence (GAS) motifs. Stat5a tetramers can bind to tandemly linked GAS motifs, but the binding site selection revealed that tetrameric binding also can be seen with a wide range of nonconsensus motifs, which in many cases did not allow Stat5a binding as a dimer. This indicates a greater degree of flexibility in the DNA sequences that allow binding of Stat5a tetramers than dimers. Indeed, in an oligonucleotide that could bind both dimers and tetramers, it was possible to design mutants that affected dimer binding without affecting tetramer binding. A spacing of 6 bp between the GAS sites was most frequently selected, demonstrating that this distance is favorable for Stat5a tetramer binding. These data provide insights into tetramer formation by Stat5a and indicate that the repertoire of potential binding sites for this transcription factor is broader than expected.

scholarly journals Is pyridoxal 5′-phosphate an affinity label for phosphate-binding sites in proteins?: The case of bovine glutamate dehydrogenase

1993 ◽  
Vol 294 (3) ◽  
pp. 835-839 ◽  
Author(s):  
Z Valinger ◽  
P C Engel ◽  
D E Metzler
Keyword(s):  
Glutamate Dehydrogenase ◽  
Binding Sites ◽  
Negative Charge ◽  
Phosphate Binding ◽  
Complete Protection ◽  
Similar Extent ◽  
Schiff’S Base ◽  
Partial Protection ◽  
Affinity Label ◽  
Characteristic Features

The effects of pyridoxal 5′-phosphate (PalP) on ox liver glutamate dehydrogenase (94% inactivation by 1.8 mM reagent at pH 7 and 25 degrees C) have been compared with those of three analogues, 5′-deoxypyridoxal (96% inactivation), pyridoxal 5′-sulphate (97%) and pyridoxal 5-methylsulphonate (94%), in order to establish whether PalP acts as an affinity label for this enzyme. Like PalP and unlike pyridoxal, which is a much less potent inactivator, none of the analogues has a free 5′-OH group to cyclize with the aldehyde function. The result with 5′-deoxypyridoxal shows that a negative charge, such as that of the phosphate group, is not required for efficient inactivation. With all four reagents, addition of an excess of cysteine or lysine led to 90-100% re-activation over 3-20 h. Dialysis also caused reactivation to a similar extent. A combination of 2.15 mM NADH, 1 mM GTP and 10 mM 2-oxoglutarate gave complete protection against PalP, but only partial protection against the analogues. 5′-Deoxypyridoxal still caused 20-25% inactivation in the presence of the protection mixture. Absorbance measurements after reduction with NaBH4 show the characteristic features of a reduced Schiff's base and allowed estimation of the extent of reaction. With all the reagents the protection mixture decreased incorporation by about 1 mol/mol, but levels of incorporation without protection varied from about 2 mol/mol for PalP up to about 5 mol/mol for 5′-deoxypyridoxal. The labelling at additional sites may explain the residual inactivation in the presence of potent protecting agents.

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