G Coupling Protein Study On The Structure Activity Relationship Of The Receptor Homology Modeling And The Effect Of The Agonist

Niacin receptor g-coupled protein receptor 109A(GPR109A) is an important target protein of the treatment of cardiovascular diseases and disorders of lipid metabolism diseases. Since GPR109 A is one membrane protein whose crystal structure has not been resolved, there are many challenges to drug design on the receptor. Based on the mouse PUMA-G crystal structure, the three dimensional structure of GPR109 A was built by using homology modeling method. Evaluated the model by using the Ramachandran Plot and Profile-3D, optimized the model through the afterburner, membrane, and method of loop, finally we obtained one stabile model and found 12 sites which might be the active sites in the optimal model. GPR109 A pyrazole agonist drug molecules were built and optimized with the steepest descent method and the conjugate gradient method to get the most stable conformation of the small drugs molecules. All the agonists were docked into each active site of the protein by Libdock method in search of the best interaction model. We analyzed the distribution of amino acid of each active site, and took 5-methyl-3-carboxylic acid as a reference drug molecule to explore the interaction force with each protein active site. This study has theoretical significance in designing G-coupled protein receptor 109 A pyrazole agonists.Three-dimensional quantitative structure-activity relationships(3D-QSAR) were used to quantitatively disclose the relationship between structure and activity of a series of G-coupled protein receptor 109 B agonists. The comparative molecular field analysis(CoMFA) and comparative molecular similarity indices analysis(CoMSIA) were employed to develop 3D-QSAR models of 46 GPR109 B agonists. The predictive capability of both 3D-QSAR models were validated by an excellent correlation coefficient using leave-one-out cross-validation q2 values and r2 values(q2 values were 0.472 and 0.498 for CoMFA and CoMSIA, r2 values were 0.920 and 0.803 for CoMFA and CoMSIA, respectively). The predictive structure-activity models show a higher ability to explain and predict the pharmaceutical data of GPR109 B agonists. The 3D-QSAR explains the dependence of pharmaceutical property upon the structures of the GPR109 B agonists. Some structure information for design of new GPR109 B agonists derivatives with higher activity has been obtained from both models.