Deciphering the GPER/GPR30-agonist and antagonists interactions using molecular modeling studies, molecular dynamics, and docking simulations

AbstractThe G-protein coupled estrogen receptor 1 GPER/GPR30 is a transmembrane seven-helix (7TM) receptor involved in the growth and proliferation of breast cancer. Due to the absence of a crystal structure of GPER/GPR30, in this work, molecular modeling studies have been carried out to build a three-dimensional structure, which was subsequently refined by molecular dynamics (MD) simulations (up to 120 ns). Furthermore, we explored GPER/GPR30's molecular recognition properties by using reported agonist ligands (G1, estradiol (E2), tamoxifen, and fulvestrant) and the antagonist ligands (G15 and G36) in subsequent docking studies. Our results identified the E2 binding site on GPER/GPR30, as well as other receptor cavities for accepting large volume ligands, through GPER/GPR30 π–π, hydrophobic, and hydrogen bond interactions. Snapshots of the MD trajectory at 14 and 70 ns showed almost identical binding motifs for G1 and G15. It was also observed that C107 interacts with the acetyl oxygen of G1 (at 14 ns) and that at 70 ns the residue E275 interacts with the acetyl group and with the oxygen from the other agonist whereas the isopropyl group of G36 is oriented toward Met141, suggesting that both C107 and E275 could be involved in the protein activation. This contribution suggest that GPER1 has great structural changes which explain its great capacity to accept diverse ligands, and also, the same ligand could be recognized in different binding pose according to GPER structural conformations.Keywords: GPR30GPR30 dockingmolecular dynamics simulationsligand recognition AcknowledgmentsThis study was conducted thanks to grants from CONACYT, México (132353), CYTED: 214RT0482, Secretaria de Investigación y Posgrado: Estimulo de desempeño en Investigación, Proyectos: 20140252 and Cooperación y Fomento de Actividades Académicas del Instituto Politécnico Nacional. We also gratefully acknowledge the scholarships from Programa Institucional de Formación de Investigadores del IPN and CONACYT to DML, postdoctoral fellowship to MMA and for visit program (June–July, 2013) of Université d'Evry-Val d'Essonne to JCB. DML thanks to CONACYT for "Beca de Movilidad Internacional".