Pharmacophore modeling, comprehensive 3D-QSAR, and binding mode analysis of TGR5 agonists
| Autor: | Pappu Srinivasan, Thangaraj Sindhu |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
Models
Molecular 0301 basic medicine Quantitative structure–activity relationship Protein Conformation Stereochemistry Quantitative Structure-Activity Relationship Biochemistry Molecular Docking Simulation Receptors G-Protein-Coupled 03 medical and health sciences Protein structure Diabetes Mellitus Humans Hypoglycemic Agents Binding site Molecular Biology Binding Sites Hydrogen bond Chemistry Imidazoles Hydrogen Bonding Cell Biology Combined approach 030104 developmental biology Pharmacophore Hydrophobic and Hydrophilic Interactions Fisher ratio |
| Zdroj: | Journal of Receptors and Signal Transduction. 37:109-123 |
| ISSN: | 1532-4281 1079-9893 |
| DOI: | 10.1080/10799893.2016.1189564 |
| Popis: | Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. Pharmacophore modeling and atom-based 3D-QSAR studies were carried out on a new series of 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides as highly potent agonists of TGR5. The generated best six featured pharmacophore model AAHHRR consists of two hydrogen bond acceptors (A): two hydrophobic groups (H) and two aromatic rings (R). The constructed 3D-QSAR model acquired excellent correlation coefficient value (R2 = 0.9018), exhibited good predictive power (Q2 = 0.8494) and high Fisher ratio (F = 61.2). The pharmacophore model was validated through Guner-Henry (GH) scoring method. The GH value of 0.5743 indicated that the AAHHRR model was statistically valuable and reliable in the identification of TGR5 agonists. Furthermore, the combined approach of molecular docking and binding free energy calculations were carried out for the 5-phenoxy-1,3-dimethyl-1H-pyrazole-4-carboxamides to explore the binding mode and interaction pattern. The generated contour maps revealed the important structural insights for the activity of the compounds. The results obtained from this study could be helpful in the development of novel and more potent agonists of TGR5. |
| Databáze: | OpenAIRE |
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