3D-pharmacophores of flavonoid binding at the benzodiazepine GABAA receptor site using 4D-QSAR analysis

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 R-6 positions of the flavonoid scaffold. Polar negative groups correctly embedded in the R-3' and/or R-6 suhstituents 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.