Molecular dynamics simulation of human estrogen receptor free and bound to morpholine ether benzophenone inhibitor

Abstract

Benzophenones (BPs) and their hydroxylated derivatives exhibited low estrogenic activity in human breast cancer cell. However, the available reported data are insufficient to describe structure modification relationship of these molecules that can be developed as a potential breast cancer drug. In this work, we present a 240-ns molecular dynamics (MD) simulation analysis on the conformational flexibility and changes of both the monomer and dimer forms of human estrogen receptor α (hERα) upon binding with the newly designed morpholine ether benzophenone (BP). The structural stability and conformational changes of an apo conformation hERα with respect to Helix 12 (H12) upon binding were determined by analyzing the H-bond formation, radius of gyration, root mean square deviation (RMSD) and root mean square fluctuation (RMSF). Molecular mechanics Poisson–Boltzmann surface area (g_mmpbsa) method was used to predict binding free energies and to estimate the energy contribution per residue to the binding energy of the complexes. Our results revealed low energy values for Leu525 and Ala350 residues in both monomer and dimer forms of hERα complexes. On the other hand, the hydrogen bonding formation between the host and the ligand in the binding pocket involved Glu353, Arg394, Asp351 and Lys529 amino acid residues, indicating that morpholine ether BP has stable interaction with hERα by mimicking the behavior of 17β-estradiol. Furthermore, transition paths analysis of H12 reveals a new stable hERα apo conformation during the simulation time.