Charge-transfer interactions in the inhibition of MAO-A by phenylisopropylamines – a QSAR study
Tóm tắt
The HOMO energies and the charges on the aromatic carbons of two sets of MAO-A-inhibiting phenylisopropylamines, one containing 4-amino substituents, were calculated by the AM1 method, in order to evaluate the importance of charge-transfer interactions between drug and enzyme. Multiple-linear regressions of the pIC50values on the calculated descriptors were performed with 33 compounds from the two sets, and separately with each set. A poor correlation was obtained when the two sets were merged, as a result of opposing trends shown by the two separate sets. These opposing trends were reconciled by invoking a partial protonation of the basic 4-amino substituents by a hydrogen-bond-donor fragment of the enzyme. The resulting analysis indicated that electron-rich rings and higher HOMO levels tended to increase activity. This model received support from the evaluation of the IMAO activity of four new phenylisopropylamines.
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