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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