4yi3 | pdb_00004yi3
Crystal structure of Gpb in complex with 4a
Structural highlights
Function[PYGM_RABIT] Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties. Publication Abstract from PubMedGlycogen phosphorylase (GP), a validated target for the development of anti-hyperglycaemic agents, has been targeted for the design of novel glycopyranosylamine inhibitors. Exploiting the two most potent inhibitors from our previous study of N-acyl-beta-D-glucopyranosylamines (Parmenopoulou et al., Bioorg. Med. Chem. 2014, 22, 4810), we have extended the linking group to -NHCONHCO- between the glucose moiety and the aliphatic/aromatic substituent in the GP catalytic site beta-cavity. The N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed by biochemical methods, revealing inhibition constant values of 4.95 microM and 2.53 microM. Crystal structures of GP in complex with these inhibitors were determined and analyzed, providing data for further structure based design efforts. A novel Linear Response - Molecular Mechanics Coulomb Surface Area (LR-MM-CBSA) method has been developed which relates predicted and experimental binding free energies for a training set of N-acyl-N -(beta-D-glucopyranosyl) urea ligands with a correlation coefficient R(2) of 0.89 and leave-one-out cross-validation (LOO-cv) Q(2) statistic of 0.79. The method has significant applications to direct future lead optimization studies, where ligand entropy loss on binding is revealed as a key factor to be considered. ADMET property predictions revealed that apart from potential permeability issues, the synthesized N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings. Glycogen phosphorylase as a target for type 2 diabetes: synthetic, biochemical, structural and computational evaluation of novel N-acyl-N -(beta-D-glucopyranosyl) urea inhibitors.,Kantsadi AL, Parmenopoulou V, Bakalov DN, Snelgrove L, Stravodimos GA, Chatzileontiadou DS, Manta S, Panagiotopoulou A, Hayes JM, Komiotis D, Leonidas DD Curr Top Med Chem. 2015;15(23):2373-89. PMID:26088352[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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