Design and synthesis of inositolphosphoglycan putative insulin mediators

The binding modes of a series of molecules, containing the glucosamine (1-->6) myo-inositol structural motif, into the ATP binding site of the catalytic subunit of cAMP-dependent protein kinase (PKA) have been analysed using molecular docking. These calculations predict that the presence of a pho...

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Bibliographic Details
Published in:Organic & biomolecular chemistry 2005-03, Vol.3 (5), p.764-786
Main Authors: López-Prados, Javier, Cuevas, Félix, Reichardt, Niels-Christian, de Paz, José-Luis, Morales, Ezequiel Q, Martín-Lomas, Manuel
Format: Article
Language:English
Subjects:
Adenosine Triphosphate - chemistry
Adenosine Triphosphate - metabolism
Animals
Binding Sites
Computer Simulation
Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors
Cyclic AMP-Dependent Protein Kinases - metabolism
Drug Design
Humans
Hypoglycemic Agents - chemical synthesis
Hypoglycemic Agents - metabolism
Hypoglycemic Agents - pharmacology
Inositol Phosphates - chemical synthesis
Inositol Phosphates - metabolism
Inositol Phosphates - pharmacology
Insulin - metabolism
Models, Molecular
Molecular Mimicry
Molecular Structure
Oligosaccharides - chemical synthesis
Oligosaccharides - metabolism
Oligosaccharides - pharmacology
Polysaccharides - chemical synthesis
Polysaccharides - metabolism
Polysaccharides - pharmacology
Protein Binding
Pyruvate Dehydrogenase (Lipoamide)-Phosphatase - chemistry
Signal Transduction - drug effects
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Summary:The binding modes of a series of molecules, containing the glucosamine (1-->6) myo-inositol structural motif, into the ATP binding site of the catalytic subunit of cAMP-dependent protein kinase (PKA) have been analysed using molecular docking. These calculations predict that the presence of a phosphate group at the non-reducing end in pseudodisaccharide and pseudotrisaccharide structures properly orientate the molecule into the binding site and that pseudotrisaccharide structures present the best shape complementarity. Therefore, pseudodisaccharides and pseudotrisaccharides have been synthesised from common intermediates using effective synthetic strategies. On the basis of this synthetic chemistry, the feasibility of constructing small pseudotrisaccharide libraries on solid-phase using the same intermediates has been explored. The results from the biological evaluation of these molecules provide additional support to an insulin-mediated signalling system which involves the intermediacy of inositolphosphoglycans as putative insulin mediators.
ISSN:1477-0520
1477-0539
DOI:10.1039/b418041k