Evaluating the accuracy of density functional theory for calculating 1H and 13C NMR chemical shifts in drug molecules
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Date
2015-01-01
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Elsevier B.V.
Abstract
The accuracy of different DFT methodologies for calculating 1H and 13C NMR chemical shifts in (R)-ispinesib, a complex drug molecule with multiple chemical groups and one stereocentre, has been evaluated. The accuracy of 6 basis sets and 16 different XC functionals was tested. In addition, we present a detailed study on the role of geometry optimisation (in gas and solution phase using a chloroform polarisable continuum model) on the accuracy of the calculated NMR spectra. NMR calculations using the double-ζ basis sets DGDZVP and 6-31++G(d,p) were found to be more accurate (and computationally more efficient) than those using larger triple-ζ basis sets. The O3LYP/DGDZVP methodology in solution phase using a geometry optimised at the same level of theory was found to be the most accurate method with mean absolute errors (MAEs) for 1H and 13C chemical shifts of 0.174 ppm and 3.972 ppm, respectively. Irrespective of the choice of XC or basis set used, complete geometry optimisation in either gas or solvent phase was found to be essential for attaining the highest accuracy in both 1H and 13C calculated chemical shifts. Finally, the role of molecular conformation was examined by calculating the Boltzmann-weighted 1H and 13C chemical shifts. Overall, we demonstrate that DFT shows exceptional promise for use in calculating the NMR chemical shifts in complex drug molecules. In the future, DFT calculations of NMR parameters are set to play an increasingly important role in drug discovery and chemical optimisation. © 2014 Elsevier B.V.
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Keywords
Nuclear magnetic resonance, Magnetic shielding, Chemical shift, Quantum mechanics, Solvation, Molecules, Drugs, Molecular structure
Citation
Hill, D. E., Vasdev, N., & Holland, J. P. (2015). Evaluating the accuracy of density functional theory for calculating 1 H and 13 C NMR chemical shifts in drug molecules. Computational and Theoretical Chemistry, 1051, 161-172. doi:https://doi.org/10.1016/j.comptc.2014.11.007