Systematic Approach to Conformational Sampling for Assigning Absolute Configuration Using Vibrational Circular Dichroism

Systematic methods that speed-up the assignment of absolute configuration using vibrational circular dichrosim (VCD) and simplify its usage will advance this technique into a robust platform technology. Applying VCD to pharmaceutically relevant compounds has been handled in an ad hoc fashion, relyin...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-01, Vol.57 (2), p.477-494
Main Authors: Sherer, Edward C., Lee, Claire H., Shpungin, Joseph, Cuff, James F., Da, Chenxiao, Ball, Richard, Bach, Richard, Crespo, Alejandro, Gong, Xiaoyi, Welch, Christopher J.
Format: Article
Language:English
Subjects:
Azetidines - chemistry
Benzoxazines - chemistry
Camphor - chemistry
Circular Dichroism - methods
Computational Biology
Drug Discovery - methods
Ezetimibe
Ibuprofen - chemistry
Molecular Conformation
Monoterpenes - chemistry
Morpholines - chemistry
Pharmaceutical Preparations - chemistry
Quantum Theory
Simvastatin - chemistry
Statistical Distributions
Stereoisomerism
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Summary:Systematic methods that speed-up the assignment of absolute configuration using vibrational circular dichrosim (VCD) and simplify its usage will advance this technique into a robust platform technology. Applying VCD to pharmaceutically relevant compounds has been handled in an ad hoc fashion, relying on fragment analysis and technical shortcuts to reduce the computational time required. We leverage a large computational infrastructure to provide adequate conformational exploration which enables an accurate assignment of absolute configuration. We describe a systematic approach for rapid calculation of VCD/IR spectra and comparison with corresponding measured spectra and apply this approach to assign the correct stereochemistry of nine test cases. We suggest moving away from the fragment approach when making VCD assignments. In addition to enabling faster and more reliable VCD assignments of absolute configuration, the ability to rapidly explore conformational space and sample conformations of complex molecules will have applicability in other areas of drug discovery.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm401600u