The QSAR Research Of GPCRs Antagonists

In this paper, computer-aided drug design methods were used to study on the two different receptor antagonists which belonged to G-protein coupled receptors (GPCR). One of them was the dopamine (DA) D3 receptor antagonist and the other was the 5 hydroxy tryptamine 6 (5-HT6) receptor antagonist. It's the first three-dimensional quantitative structure-activity relationship (3D-QSAR) study for these new synthesized antagonists. The main methods we used in the course of studying these two types of antagonists were 3D-QSAR, homology modeling, molecular docking and molecular dynamics simulation. Finally we built the models with proper reliability and predictive capacity. The specific works we carried out are as following two aspects:Through the first study of 109 DA D3 receptor antagonists with 11 different skeleton types. After various modeling processes, the finally results showed that the receptor-based 3D-QSAR models have proper predictive capacity. In addition, a combined analysis between contour maps and molecular dynamics results with a homology protein model shows that:(1) R1 substituent (at position-2 of ring-A) and R3 substituent in ring-D are key regions to design of antagonist with higher activity; (2) more bulky R1 substituent (at position-2 of ring-A) of antagonist may well fit in the binding pocket; (3) hydrophobicity represented by MlogP is important for building satisfactory 3D-QSAR models, moreover, R1 substituent in ring-A and position-15 in ring-C have hydrophobic groups are beneficial to enhance the activities; (4) during the molecular docking and molecular dynamics simulation we found that the key amino acids of the binding pocket are CYS101, ILE105, LEU106, VAL151, PHE175, PHE184, PRO254 and ALA251.Through the study of 143 new synthesized 5-HT6 receptor antagonists that using 3D-QSAR modeling methods, our results show that both the optimal CoMFA and CoMSIA models are reliable with proper predictive capacity. In addition, the analysis about the CoMFA and CoMSIA contour maps shows that:(1) the bulky and negatively charged R2 substituent will improve the activity; (2) hydrophobic groups in both R3 and R1 substituent at the benzene ring benefit the activity; (3) hydrogen bond acceptor substituent in R2 and hydrogen bond donor group in R3 will also lead to high activity.During our study, on the one hand it reveals the structural features about the GPCRs and small ligand molecule, and making it possible to better understands the mechanism between the receptor and ligand. On the other hand it is helpful to guide for the synthesis of new antagonist molecules.