التفاصيل البيبلوغرافية
| العنوان: |
Glycogen phosphorylase as a target for type 2 diabetes: Synthetic, biochemical, structural and computational evaluation of novel N-acyl-N´-(β-D-glucopyranosyl) urea inhibitors |
| المؤلفون: |
Kantsadi, A. L., Parmenopoulou, V., Bakalov, D. N., Snelgrove, L., Stravodimos, G. A., Chatzileontiadou, D. S. M., Manta, S., Panagiotopoulou, A., Hayes, J. M., Komiotis, D., Leonidas, D. D. |
| المصدر: |
http://www.scopus.com/inward/record.url?eid=2-s2.0-84940906115&partnerID=40&md5=aba470d983c24f037d6efef24b53c716Test. |
| سنة النشر: |
2015 |
| المجموعة: |
University of Thessaly Institutional Repository / Ιδρυματικό Αποθετήριο Πανεπιστημίου Θεσσαλίας |
| مصطلحات موضوعية: |
Binding free energy, Diabetes type 2, Glycogen phosphorylase, Linear response methods, N-acyl-β-D-glucopyranosyl ureas, X-ray crystallography, n (e) 3 (4 isopropylphenyl)acryloyl n΄ (2,3,4,6 tetra oacetyl beta D glucopyranosyl) urea, n (e) 3 (4 isopropylphenyl)acryloyl n΄ (beta D glucopyranosyl) urea, n (e) 3 (biphenyl 4 yl)acryloyl n΄ (2,3,4,6 tetra oacetyl beta D glucopyranosyl) urea, n (e) 3 (biphenyl 4 yl)acryloyl n΄ (beta D glucopyranosyl) urea, n acetyl n' (beta D glucopyranosyl) urea inhibitor, n acyl n΄ beta D glucopyranosylurea, n acyl n΄ 2,3,4,6 tetra o acetyl beta D glucopyranosylurea, unclassified drug, Article, binding affinity, carbon nuclear magnetic resonance, chemical structure, drug binding site, drug efficacy, drug screening, entropy, enzyme kinetics, mathematical computing, molecular docking, non insulin dependent diabetes mellitus, nonhuman, proton nuclear magnetic resonance, rabbit, reaction optimization |
| الوصف: |
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. © 2015 Bentham Science Publishers. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| تدمد: |
15680266 |
| العلاقة: |
http://hdl.handle.net/11615/28887Test |
| الإتاحة: |
http://hdl.handle.net/11615/28887Test |
| رقم الانضمام: |
edsbas.66C24BCB |
| قاعدة البيانات: |
BASE |
