ISSN:
0020-7608
Keywords:
Computational Chemistry and Molecular Modeling
;
Atomic, Molecular and Optical Physics
Source:
Wiley InterScience Backfile Collection 1832-2000
Topics:
Chemistry and Pharmacology
Notes:
Experimentally measured rates for the oxidation of p-substituted benzyl amines by bovine monoamine oxidase type B (MAO-B) derived from the literature were examined with respect to the effects of molecular (semiempirically (AM1) derived) electronic, steric, and lipophilicity parameters. These properties included vertical and adiabatic ionization potential, LUMO energy, the LUMO-HOMO difference, molecular hardness, absolute electronegativity, calculated log P values, molecular volume, surface area, and ovality. Substrate oxidation rates (log kcat/Km) were found to correlate with molecular ovality and vertical ionization potential while the rate of enzymatic (flavin) reduction associated with substrate oxidation (log kred) was described by a two-parameter model containing an ovality and an absolute electronegativity term. These results are consistent with an initial one-electron substrate oxidation mechanism. In previous work, use of classical Hansch analysis suggested that electronic terms were not important in the enzymatic reactions. This discrepancy may be related to nontransferability inherent in fragment approaches which assume that the substituent of interest behaves similarly in all molecular scaffolds. Analysis of substrate binding (log Kd) to the enzyme was described by a two-parameter model containing a calculated log P term as well as LUMO energy. The significant correlation found with LUMO energy is consistent with studies suggesting that this property is important for drug-receptor interactions. © 1995 John Wiley & Sons, Inc.
Additional Material:
8 Tab.
Type of Medium:
Electronic Resource
URL:
http://dx.doi.org/10.1002/qua.560560718
