CP-MLR/PLS directed QSAR study on the glutaminyl cyclase inhibitory activity of imidazoles: rationales to advance the understanding of activity profile

The glutaminyl cyclase inhibitory activity of a series of imidazoles has been analyzed through combinatorial protocol in multiple linear regressions (CP-MLR) and partial least square using different topological and structural descriptors. The QC activity was found to be correlated with 2D-autocorrelation (2DAUTO) and atom centered fragments (ACF) descriptors. The descriptor from 2DAUTO class showed that molecular structure frames of one, six and seven path length associated with atomic van der Waals volumes and polarizability hold scope for modulating QC inhibitory activity. The ACF descriptors suggested that the unsubstituted alkyl fragments and methyl substituted imidazole ring are favorable, while unsaturation in the same and C=N-C≡N are unfavorable for activity. The molar refractivity (MR) is conducive for activity. The descriptors identified in the study collectively highlight the significance of molecular volume and polarizability to the QC inhibitory activity of imidazoles. The models are statistically significant and showed good predictivity.