Exploring the Binding Mechanism of Inverse Agonists against Estrogen-related receptor alpha with multiscale molecular modeling
Konda Reddy Karnati, Yixuan Wang*
Department of Chemistry and Forensic Science, Albany State University, Albany, GA 31705, USA
Email: yixuan.wang@asurams.edu
Estrogen-related receptor alpha (ERRα) is an orphan nuclear receptor belonging to NR3 B subgroup that displays constitutively active transcriptional activities. A clear understanding of ERRα-inverse agonist activity is likely to shed light on unresolved aspects of Estrogen Receptor signaling and may validate ERRα as a useful therapeutic target in breast cancer. In the current study, we have explored the binding mode of inverse agonists targeting ERRα. Molecular docking, all atom molecular dynamics (MD) simulations and Molecular Mechanics PoissonBoltzmann Surface Area (MMPBSA) binding free energy calculations were carried to assess the binding mode and binding affinity of inverse agonists. For the residues with 5Å, QM/MM was employed to more accurately investigate their binding with the estrogen. It was found inverse agonists bind with H3 and H11 regions in ERRα ligand binding pocket. MD simulations show that the binding of inverse agonists to ERRα, where H12 adopts a well-defined position in the coactivator groove, the place where PGC-1α binds to ERRα. Understanding the binding mode of inverse agonists will provide valuable guidance for rational drug design of ERRα.