Molecular Dynamics Simulations Based on 1-Phenyl-4-Benzoyl-1-Hydro-Triazole ERRα Inverse Agonists

Estrogen-related receptor alpha (ERR alpha), which is overexpressed in a variety of cancers has been considered as an effective target for anticancer therapy. ERR alpha inverse agonists have been proven to effectively inhibit the migration and invasion of cancer cells. As few crystalline complexes have been reported, molecular dynamics (MD) simulations were carried out in this study to deepen the understanding of the interaction mechanism between inverse agonists and ERR alpha. The binding free energy was analyzed by the MM-GBSA method. The results show that the total binding free energy was positively correlated with the biological activity of an inverse agonist. The interaction of the inverse agonist with the hydrophobic interlayer composed of Phe328 and Phe495 had an important impact on the biological activity of inverse agonists, which was confirmed by the decomposition of energy on residues. As Glu331 flipped and formed a hydrogen bond with Arg372 in the MD simulation process, the formation of hydrogen bond interaction with Glu331 was not a necessary condition for the compound to act as an inverse agonist. These rules provide guidance for the design of new inverse agonists.

Automated summary

ERRα inverse agonists are effective in inhibiting the migration and invasion of cancer cells, and the total binding free energy is positively correlated with their biological activity. The interaction of inverse agonists with the hydrophobic interlayer composed of Phe328 and Phe495 plays a crucial role in determining their biological activity.