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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.

SUBMITTER: McGaughey G

PROVIDER: S-EPMC3927067 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

McGaughey Georgia G Bayly Christopher I CI Cox Christopher D CD Schreier John D JD Breslin Michael J MJ Bogusky Michael M Pitzenberger Steve S Ball Richard R Coleman Paul J PJ

Journal of computer-aided molecular design 20140101 1

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 ...[more]

PMID: 24488306

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Project description:Background and Significance: Parallel-group randomized controlled trials (PG-RCTs) are the gold standard for detecting differences in mean improvement across treatment conditions. However, PG-RCTs provide limited information about individuals, making them poorly optimized for quantifying the relationship of a biomarker measured at baseline with treatment response. In N-of-1 trials, an individual subject moves between treatment conditions to determine their specific response to each treatment. Aggregated N-of-1 trials analyze a cohort of such participants, and can be designed to optimize both statistical power and clinical or logistical constraints, such as allowing all participants to begin with an open-label stabilization phase to facilitate the enrollment of more acutely symptomatic participants. Here, we describe a set of statistical simulation studies comparing the power of four different trial designs to detect a relationship between a predictive biomarker measured at baseline and subjects' specific response to the PTSD pharmacotherapeutic agent prazosin. Methods: Data was simulated from 4 trial designs: (1) open-label; (2) open-label + blinded discontinuation; (3) traditional crossover; and (4) open label + blinded discontinuation + brief crossover (the N-of-1 design). Designs were matched in length and assessments. The primary outcome, analyzed with a linear mixed effects model, was whether a statistically significant association between biomarker value and response to prazosin was detected with 5% Type I error. Simulations were repeated 1,000 times to determine power and bias, with varied parameters. Results: Trial designs 2 & 4 had substantially higher power with fewer subjects than open label design. Trial design 4 also had higher power than trial design 2. Trial design 4 had slightly lower power than the traditional crossover design, although power declined much more rapidly as carryover was introduced. Conclusions: These results suggest that an aggregated N-of-1 trial design beginning with an open label titration phase may provide superior power over open label or open label and blinded discontinuation designs, and similar power to a traditional crossover design, in detecting an association between a predictive biomarker and the clinical response to the PTSD pharmacotherapeutic prazosin. This is achieved while allowing all participants to spend the first 8 weeks of the trial on open-label active treatment.

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

Publications

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

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