Rapid quantum mechanical models for the computational estimation of C-H bond dissociation energies as a measure of metabolic stability.

John L. Lewin, Christopher J. Cramer

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Several relatively inexpensive levels of theory are surveyed together with alternative algorithmic methods for the estimation of C-H bond dissociation energies (BDEs), 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) over 32 diverse C-H bonds. An alternative method for correlating the AM1 parabolic force constant from a two-point unrelaxed potential provides only a slightly decreased accuracy and is computationally particularly inexpensive. Both methods should prove to be useful for the rapid in silico screening of drug-like molecules for metabolic stability to C-H bond oxidizing enzymes.

Original languageEnglish (US)
Pages (from-to)128-135
Number of pages8
JournalMolecular pharmaceutics
Volume1
Issue number2
StatePublished - Jan 1 2004

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