Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs

Abstract

Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported.

Fig. 1

2D and 3D small molecule low energy, computationally-derived representation of Compound 1 (OX1R Ki = 1.2 nM, OX2R Ki = 0.8 nM. Individual replicates for all data shown herein are included in the supplementary material. Only the mean is reported

Fig. 2

2D representation of chemical structures and corresponding 3D low energy conformation of ligands

Fig. 3

2D representation of compound 7 which became our clinical candidate (MK-4305) and later termed Suvorexant (OX1R Ki = 0.54 nM, OX2R Ki = 0.35 nM)

Fig. 4

X-Ray structure of Suvorexant (MK-4305/Compound 7)

Fig. 5

RMSD between the non-hydrogen atoms of the same compound in the bound (complex) and unbound (no complex) crystal structure as a function of molecular weight. The value for Januvia^® is circled in red

Fig. 6

Small-molecule crystal structure colored in orange (carbon atoms) of Januvia^® superposed with bound crystal structure of Januvia^® colored in yellow (carbon atoms) complexed in DPPIV

Fig. 7

Conformer free energies versus relative energies (force field + solvation) for accessible conformations of 1. Blue stars Extended conformations; green circles F2F conformations. The model for the bioactive conformation (F2F) is outlined in red. There are extended conformers close in free energy

Fig. 8

Conformer free energies versus relative energies (force field and solvation) for accessible conformations of 7. Blue stars Extended conformations; green circles F2F conformations. The minimum corresponding to the X-ray conformation (extended) is outlined in red