Computational studies on horseshoe shape pocket of human orexin receptor type 2 and boat conformation of suvorexant by molecular dynamics simulations

The FDA approved drug suvorexant binds to the horseshoe shape pocket of OX₂R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX₂R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX₂R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX₂R in complex with antagonist suvorexant are chosen to perform molecular dynamics (MD) simulations, QM/MM, and MMGBSA calculations. By comparison with the wild type of OX₂R, the results show the 1,2,3-triazole and p-toluamide groups of suvorexant are changed in the N324A mutant of OX₂R during 200 ns MD simulations. The QM/MM and weak interaction analysis are employed to calculate the non-covalent bonds interaction between suvorexant and key residues in the wild type and N324A mutant of OX₂R. The MMGBSA calculations indicate the entropy energy is an important influence factor for suvorexant affinity in the distorted horseshoe shape pocket of OX₂R. Our results not only show the horseshoe shape pocket of OX₂R is the necessary conformation for the binding of antagonist suvorexant, but also give the important sites and structural features for antagonist design of OX₂R.