Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy

Thomson, Stephen A.; Banker, Pierette; Bickett, D. Mark; Boucheron, Joyce A.; Carter, H.L.; Clancy, Daphne C.; Cooper, Joel P.; Dickerson, Scott H.; Garrido, Dulce; Nolte, R.T.; Peat, Andrew J.; Sheckler, Lauren R.; Sparks, Steven M.; Tavares, Francis X.; Wang, L.; Wang, T.Y.; Weiel, James E.

doi:10.1016/j.bmcl.2008.12.085

Cited by 18 publications

(12 citation statements)

References 19 publications

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“…The X-ray crystal structure of hGP in complex with inhibitor GSK254 was obtained from Protein Data Bank (PDB) [17].…”

Section: Data Setmentioning

confidence: 99%

Predicting Cross-Reactivity from Computational Studies for Pre-evaluation of Specific Hepatic Glycogen Phosphorylase Inhibitors

Konkimalla

2015

Bioinformatics and Biomedical Engineering

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Abstract. Over the past decade, only very few drugs made it to the market this bottleneck is mainly attributed due to their failures at the pre-clinical and clinical stages of drug development pipeline. Several bioinformatics tools and molecular docking approaches have enormously contributed to the rational design of cost-effective, efficacious and novel lead molecules. Research over past few decades resulted in the development of virtual screening methods, where several million compounds from various databases can be screened in limited time very effectively. Majority of the investigations performed so far focuses only on a single target ruling out the possibility that the same ligand can bind to an offtarget with a high-sequence similarity (especially isozymes) leading to unwanted effects. Glycogen phosphorylases (GP) are phosphorylase enzymes that are implicated in several metabolic disorders such as type-2 diabetes and also other disease like cancer and coronary disease. GP are present both in muscle and hepatic tissue as isozymes and many inhibitors of GP (GPi) due to lack of specificity cross-react between both these isozymes and lead to delirious sideeffects. Taking together the role and features of GP, the objective of the current work is to develop a strategy in molecular docking approach to pre-evaluate specificity of GPi using in silico derived pentacyclic triterpenes.

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“…The X-ray crystal structure of hGP in complex with inhibitor GSK254 was obtained from Protein Data Bank (PDB) [17].…”

Section: Data Setmentioning

confidence: 99%

Predicting Cross-Reactivity from Computational Studies for Pre-evaluation of Specific Hepatic Glycogen Phosphorylase Inhibitors

Konkimalla

2015

Bioinformatics and Biomedical Engineering

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“…Not surprisingly, structural studies with various ligands are gradually increasing our understanding of the dynamics and allostery of oligomeric structures of glycogen phosphorylases, like e.g. rabbit muscle [64] and human liver [65,66] variants.…”

Section: Gt-b Foldsmentioning

confidence: 99%

Crystal structures of eukaryote glycosyltransferases reveal biologically relevant enzyme homooligomers

Harrus

Kellokumpu

Glumoff

2017

Cell. Mol. Life Sci.

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Glycosyltransferases (GTases) transfer sugar moieties to proteins, lipids or existing glycan or polysaccharide molecules. GTases form an important group of enzymes in the Golgi, where the synthesis and modification of glycoproteins and glycolipids take place. Golgi GTases are almost invariably type II integral membrane proteins, with the C-terminal globular catalytic domain residing in the Golgi lumen. The enzymes themselves are divided into 103 families based on their sequence homology. There is an abundance of published crystal structures of GTase catalytic domains deposited in the Protein Data Bank (PDB). All of these represent either of the two main characteristic structural folds, GT-A or GT-B, or present a variation thereof. Since GTases can function as homomeric or heteromeric complexes in vivo, we have summarized the structural features of the dimerization interfaces in crystal structures of GTases, as well as considered the biochemical data available for these enzymes. For this review, we have considered all 898 GTase crystal structures in the Protein Data Bank and highlight the dimer formation characteristics of various GTases based on 24 selected structures.

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“…The ligands were removed from their X-ray structure and minimised prior to being docked into their appropriate site using Surflex-Dock. Validation of the site involved docking ligand 30, 31 and 32 in the purine and indole sites [7] (PDB ID: 1L5Q) and AMP site [58] (PDB ID: 3DDS) respectively. The RMSD between each ligand and its docked pose was found; 0.5Å (AMP), 0.1Å (purine) and 2.0Å (indole).…”

Section: Validation Of Modelmentioning

confidence: 99%

“…In the present fragment library, further analysis of the subset of 5, 7, 9-13 and 19, using LE and LELP indicated that compound 7 was a promising hit, with compounds 5 and 11 being second tier hits. To potentially facilitate a level of understanding, the molecular interactions of 5, 7, 9-13 and 19with human liver glycogen phosphorylase was explored in silico, whilst acknowledging that weak binding to GP binding sites is likely to be observed by the virtue of the low MW of compounds Validation of the site was carried out by docking ligands 30, 31 and 32, which are selective for each site, into the purine and indole sites[7] (PDB ID: 1L5Q) and AMP site[58] (PDB ID: 3DDS) respectively, of human liver GP from the RCSB Protein Data Bank. Human liver GP was selected for study since this isoform presents the most important target for GP inhibition.…”

mentioning

confidence: 99%

Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors

Schweiker¹,

Loughlin²,

Lohning³

et al. 2014

European Journal of Medicinal Chemistry

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A series of morpholine substituted amino acids (phenylalanine, leucine, lysine and glutamic acid) was synthesized. A fragment-based screening approach was then used to evaluate a series of small heterocycles, including morpholine, oxazoline, dihydro-1,3-oxazine, tetrahydro-1,3-oxazepine, thiazoline, tetrahydro-1,3-pyrimidine, tetrahydro-1,3-diazepine and hexahydro-1H-benzimidazole, as potential inhibitors of Glycogen Phosphorylase a. Thiazoline 7 displayed an improved potency (IC50 of 25 μM) and had good LE and LELP values, as compared to heterocycles 1, 5, 9-13 and 19 (IC50 values of 1.1 mM-23.9 mM). A docking study using the crystal structure of human liver Glycogen Phosphorylase, provided insight into the interactions of heterocycles 5, 7, 9-13 and 19 with Glycogen Phosphorylase.

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Anthranilimide based glycogen phosphorylase inhibitors for the treatment of type 2 diabetes. Part 3: X-ray crystallographic characterization, core and urea optimization and in vivo efficacy

Cited by 18 publications

References 19 publications

Predicting Cross-Reactivity from Computational Studies for Pre-evaluation of Specific Hepatic Glycogen Phosphorylase Inhibitors

Predicting Cross-Reactivity from Computational Studies for Pre-evaluation of Specific Hepatic Glycogen Phosphorylase Inhibitors

Crystal structures of eukaryote glycosyltransferases reveal biologically relevant enzyme homooligomers

Synthesis, screening and docking of small heterocycles as Glycogen Phosphorylase inhibitors

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