دورية أكاديمية
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
| العنوان: | 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 |
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| 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: | Current Topics in Medicinal Chemistry ; ://WOS:000360375600003 |
| سنة النشر: | 2015 |
| المجموعة: | University of Thessaly Institutional Repository / Ιδρυματικό Αποθετήριο Πανεπιστημίου Θεσσαλίας |
| مصطلحات موضوعية: | Glycogen phosphorylase, X-ray crystallography, Diabetes type 2, N-acyl-beta-D-glucopyranosyl ureas, Binding free energy, Linear response, methods, INTERACTION ENERGY METHOD, BIOLOGICAL ASSESSMENT, DEVELOPMENT SETTINGS, ESTIMATE SOLUBILITY, BINDING AFFINITIES, DRUG SOLUBILITY, DOCKING POSES, DESIGN, PERMEABILITY, DISCOVERY, Chemistry, Medicinal |
| 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-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 mu M and 2.53 mu M. 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | unknown |
| تدمد: | 1568-0266 |
| العلاقة: | http://hdl.handle.net/11615/28886Test |
| DOI: | 10.2174/1568026615666150619142253 |
| الإتاحة: | https://doi.org/10.2174/1568026615666150619142253Test http://hdl.handle.net/11615/28886Test |
| رقم الانضمام: | edsbas.11C57B5D |
| قاعدة البيانات: | BASE |
| تدمد: | 15680266 |
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| DOI: | 10.2174/1568026615666150619142253 |