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 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.
López-Prados
Javier
J
Grupo de Carbohidratos, Instituto de Investigaciones Químicas, CSIC, Américo Vespucio s/n, 41092, Sevilla, Spain.
Cuevas
Félix
F
Reichardt
Niels-Christian
NC
de Paz
José-Luis
JL
Morales
Ezequiel Q
EQ
Martín-Lomas
Manuel
M
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D007295:Inositol Phosphates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D008958:Models, Molecular; D018716:Molecular Mimicry; D015394:Molecular Structure; D009844:Oligosaccharides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011134:Polysaccharides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects
D007004:Hypoglycemic Agents; D007295:Inositol Phosphates; D007328:Insulin; D009844:Oligosaccharides; D011134:Polysaccharides; C028039:inositol phosphate glycan; D000255:Adenosine Triphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D011769:Pyruvate Dehydrogenase (Lipoamide)-Phosphatase