Pharmacophore modeling, comprehensive 3D-QSAR, and binding mode analysis of TGR5 agonists.
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.
a Molecular Biology Lab, Department of Bioinformatics , Alagappa University , Karaikudi , Tamilnadu , India.
Thangaraj
T
Sindhu
a Molecular Biology Lab, Department of Bioinformatics , Alagappa University , Karaikudi , Tamilnadu , India.
Pappu
P
Srinivasan
D001665:Binding Sites; D003920:Diabetes Mellitus / Q000188:drug therapy*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000627:therapeutic use; D007093:Imidazoles / Q000737:chemistry* / Q000627:therapeutic use; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D011487:Protein Conformation / Q000187:drug effects; D021281:Quantitative Structure-Activity Relationship; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000737:chemistry* / Q000627:therapeutic use
C473772:GPBAR1 protein, human; D007004:Hypoglycemic Agents; D007093:Imidazoles; D043562:Receptors, G-Protein-Coupled; C029899:imidazole
3D-QSAR; IFD; TGR5; anti-diabetic drugs; pharmacophore modeling