Molecular Docking And 3d-qsar Research Of Selective Estrogen Receptor Modulators

Estrogen receptor(ER) is a key protein in estrogen signaling pathway, which plays a critical role in human growth and tissue metabolism. ER can be divided into two subtypes, namely ERαand ERβ. Selective estrogen receptor modulators (SERMs) is a special class of compounds, which have different effects on the organisms by the interactions with different receptors. The effects induced by the SERMs are also found of tissue specificity. So, it is very important to explore the interaction mechanism between SERMs and ER and the quantitative structure-activity relationship (QSAR), in order to develope new SERMs with high activities and tissue specificity.In this paper, molecular docking was employed in the inter-molecule interaction studies on 5 SERMs systems, i.e. quinoline derivatives, benzoxepin derivatives, salicylaldximes derivatives, pyrimidines and pyrazines derivatives as well as indazole derivatives. Based on the docking results, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed to the studies of quantitative structure-activity relationships. The research results are as follows:①Quinoline derivatives: molecular docking results show that the main interactions between ligand and ERαare hydrogen bonds and hydrophobic interactions, while the main interactions with ERβare hydrogen bonds, hydrophobic, and electrostatic interactions. The results also show that the electrostatic field may play a more important role in ERβQSAR models than that in ERα, and that negative charged substitution in R4 position is favorable to the selective specificity for ERβ. Based on the docking conformation, CoMFA and CoMSIA models were established. The best ERαmode is the CoMSIA model established by the electrostatic (38.7%)and hydrophobic field(48.9%). The r2, q2(LOO), and r2pred of this best model are 0.968, 0.763, and 0.566, respectively. The best ERβCoMSIA model is established by steric(12.0%), electrostatic(41.6%), hydrophobic field(25.5%) and hydrogen bond donor field (20.9%). The r2, q2(LOO) and r2pred of that best model are 0.958, 0.669 and 0.741, respectively.②Benzoxepin derivatives: molecular docking results show that the main interactions between ligand and ERαare hydrogen-bond interactions, hydrophobic interactions, and the steric effects between R1 substituent and His425. The main interactions with ERβare hydrogen-bond, hydrophobic, electrostatic interactions, and the steric effects between F substituent of B ring and Glu305. The results also show that it is favorable to the ERβbinding affinities when D and E ring interacte with the hydrophobic residues Ile373, Phe377 and Gly472, which contribute to the ERβselective specificity. Based on the docking conformation, CoMFA and CoMSIA models were established. The best mode of ERαis the CoMSIA model established by the hydrophobic field, and the r2, q2(LOO) and r2pred are 0.977, 0.583 and 0.508, respectively. The best CoMSIA model of ERβis established by electrostatic field (12.0%) and hydrogen bond donor field (41.6%), and the r2, q2(LOO) and r2pred are 0.778, 0.508, and 0.593, respectively.③Salicylaldximes derivatives: molecular docking results show that the main interactions between ligand and ERαor ERβare hydrogen-bond and hydrophobic interactions. Hydrophilic interactions between ligands and residues Glu353 and Arg394 causes a sharp decrease in ERαactivities. And the steric effects between R4 substituent and hydrophobic residues Ile376, Gly472, Leu476 and Leu477 are also unfavorable to ERβactivities. Besides, electrostatic field contributions to the models may play a more important role in ERβthan that in ERα. Based on the docking conformations, CoMFA and CoMSIA models are established. The best ERαmode is the CoMSIA model established by the electrostatic field (39%) and hydrogen-bond donor (61%), and the r2, q2(LOO) and r2pred are 0.932, 0.666, and 0.589, respectively. The best ERβCoMSIA model is established by steric field (29.5%) and electrostatic field (70.5%), of which the r2, q2(LOO) and r2pred are 0.904, 0.503, and 0.944, respectively.④Pyrimidines and pyrazines derivatives: molecular docking results showed that the the main interactions between ligand and ERαor ERβwere hydrogen bonds and hydrophobic interactions. It is benefit to increase Van der Waals force of the position 6 to increase ERαbinding activity. Based on the docking conformation, CoMFA and CoMSIA models were established. The best ERαmode is the CoMSIA model, which c established by the steric field (47.6%) and electrostatic field(52.4%), the r2, q2(LOO) and r2pred were0.624, 0.949 and 0.410, respectively. The best ERβCoMSIA model is established by electrostatic field (37.8%) and hydrogen bond donor (62.2%), the r2, q2(LOO) and r2pred were 0.611, 0.948 and 0.644, respectively.⑤Indazole derivatives: molecular docking results show that the main interactions between ligand and ERα/ERβare hydrogen-bond and hydrophobic interactions. The hydrophobic groups in R4 position are favorable to the ERαbinding activities, while the steric effectes between R4 group and ERβmay contribute to the ERβselective specificity. Based on the docking conformation, CoMFA and CoMSIA models are established. The best ERαmode is the CoMSIA model comsisted of the steric field (9.1%), electrostatic field (52.1%), and hydrogen bond donor (38.7%), of which the r2, q2(LOO), and r2pred were 0.963, 0.834, and 0.365, respectively. The best ERβCoMSIA model is established by steric field (8.2%), hydrophobic (34.4%), and hydrogen-bond donor field (57.4%), of which the r2, q2(LOO), and r2pred are 0.984, 0.9723, and 0.543, respectively.