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 OX 2 R with the boat conformation. The horseshoe shape pocket plays an important role on the biological activity of OX 2 R in the cell membrane. To study the binding mechanism between the horseshoe shape pocket of OX 2 R and boat conformation of suvorexant, the crystal structures of wild type and N324A mutant of OX 2 R 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 OX 2 R, the results show the 1,2,3‐triazole and p ‐toluamide groups of suvorexant are changed in the N324A mutant of OX 2 R 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 OX 2 R. The MMGBSA calculations indicate the entropy energy is an important influence factor for suvorexant affinity in the distorted horseshoe shape pocket of OX 2 R. Our results not only show the horseshoe shape pocket of OX 2 R is the necessary conformation for the binding of antagonist suvorexant, but also give the important sites and structural features for antagonist design of OX 2 R.