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

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• 作者：Georgia McGaughey (1) (5)
  Christopher I. Bayly (2)
  Christopher D. Cox (3)
  John D. Schreier (3)
  Michael J. Breslin (3)
  Michael Bogusky (3)
  Steve Pitzenberger (3)
  Richard Ball (4)
  Paul J. Coleman (3)
  
• 关键词：Suvorexant ; Conformational analysis ; Free energy ; ROCS
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：2014
• 出版时间：January 2014
• 年：2014
• 卷：28
• 期：1
• 页码：5-12
• 全文大小：1,001 KB
• 作者单位：Georgia McGaughey (1) (5)
  Christopher I. Bayly (2)
  Christopher D. Cox (3)
  John D. Schreier (3)
  Michael J. Breslin (3)
  Michael Bogusky (3)
  Steve Pitzenberger (3)
  Richard Ball (4)
  Paul J. Coleman (3)
  
  1. Chemistry, Modeling and Informatics, Merck Research Laboratories, WP53F-301, West Point, PA, 19486, USA
  5. Vertex Pharmaceuticals, 50 Northern Ave, Boston, MA, 02210, USA
  2. OpenEye Scientific Software, Santa Fe, NM, 87508, USA
  3. Discovery Chemistry, Merck Research Laboratories, WP14-3, West Point, PA, 19486, USA
  4. Analytical Chemistry, Merck Research Laboratories, Rahway, NJ, 07065, USA
  
• ISSN：1573-4951

文摘

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.