QSAR and Binding Model for Inhibition of Rat Liver Catechol‐O‐Methyl‐Transferase by 1,5‐Substituted‐3,4‐Dihydroxybenzenes

Abstract

Abstract Quantitative structure‐activity analysis was carried out for in vitro inhibition of rat liver catechol‐O‐methyl‐transferase by a series of 1,5‐substituted‐3,4‐dihydroxybenzenes. Linear regression analysis showed high correlation of inhibitory activity with both empirical electronic substituent parameters and quantum chemical descriptors. The combined effect of both substituents on lowering the pKa values of catechol hydroxyls and the energy of the lowest unoccupied molecular orbital appeared to be the most important determinant of increasing activity. Both substituents seemed to be also directly involved in binding. Hydrophobicity of the substituent at position 1 and the electronic structure of the substituent at position 5 were correlated with activity. A model for binding interactions of inhibitors was postulated on the basis of the QSAR equations derived.