Rapid Quantum Mechanical Models for the Computational Estimation of C-H Bond Dissociation Energies as a Measure of Metabolic Stability

Lewin, J. L.; Cramer, C. J.
Mol. Pharmaceutics 2004, 1, 128.

Several relatively inexpensive levels of theory are surveyed together with alternative algorithmic methods for the estimation of C-H bond dissociation energies, such energies being useful for the prediction of metabolic stability in drug-like molecules. In particular, bond-stretching potentials of several C-H bonds are computed using the AM1, PM3, HF/MIDI!, and B3LYP/MIDI! levels of electronic structure theory and selected points are fit to Morse and parabolic potentials. BDEs computed by an AM1 fit to the Morse function show the smallest mean unsigned error in prediction (±3-4 kcal mol^-1) over 32 diverse C-H bonds. An alternative method correlating the AM1 parabolic force constant from a 2-point unrelaxed potential provides only a slightly decreased accuracy and is computationally particularly inexpensive. Both methods should prove useful for the rapid in silico screening of drug-like molecules for metabolic stability to C-H oxidizing enzymes.

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