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

McGaughey G, Bayly CI, Cox CD, Schreier JD, Breslin MJ, Bogusky M, Pitzenberger S, Ball R, Coleman PJ - J. Comput. Aided Mol. Des. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry, Modeling and Informatics, Merck Research Laboratories, WP53F-301, West Point, PA, 19486, USA, georgia_mcgaughey@vrtx.com.

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.

Show MeSH
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
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Related In: Results  -  Collection


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Fig6: 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

Mentions: The literature also suggests that while the predicted low energy solvated structure is often the bioactive this is not always true [17, 18] (Fig. 6).Fig. 6


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

McGaughey G, Bayly CI, Cox CD, Schreier JD, Breslin MJ, Bogusky M, Pitzenberger S, Ball R, Coleman PJ - J. Comput. Aided Mol. Des. (2014)

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
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3927067&req=5

Fig6: 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
Mentions: The literature also suggests that while the predicted low energy solvated structure is often the bioactive this is not always true [17, 18] (Fig. 6).Fig. 6

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Chemistry, Modeling and Informatics, Merck Research Laboratories, WP53F-301, West Point, PA, 19486, USA, georgia_mcgaughey@vrtx.com.

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.

Show MeSH