Glycogen 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-β-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 β-cavity. The N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors were synthesized and their efficiency assessed
by biochemical methods, revealing inhibition constant values of 4.95 µM and 2.53 µM. 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´-(β-D-glucopyranosyl) urea ligands
with a correlation coefficient R2 of 0.89 and leave-one-out cross-validation (LOO-cv) Q2 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´-(β-D-glucopyranosyl) urea inhibitors have drug-like potential without any toxicity warnings.
Keywords: Glycogen phosphorylase, X-ray crystallography, Diabetes type 2, N-acyl-β-D-glucopyranosyl ureas, Binding free
energy, Linear response methods.
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