3D-Pharmacophores of Flavonoid Binding at the Benzodiazepine GABAA Receptor Site Using 4D-QSAR Analysis

Abstract

4D-QSAR analysis was applied to a training set of 38 flavonoids where affinity constants, Ki, to the GABA_A benzodiazepine receptor site, BzR, were determined. It was found that the −logKi values of the compounds are highly dependent on the size and electrostatics character of the substituents at the R_3‘ and R₆ positions of the flavonoid scaffold. Polar negative groups correctly embedded in the R_3‘ and/or R₆ substituents are predicted to increase −logKi values. A planar conformation of the flavonoid scaffold was found not to be a requirement for the flavonoids to be active. A test set of four compounds was used to evaluate the predictivity of the 4D-QSAR models.