Deciphering the Calculated QSAR Properties of Polyaryl Compounds that Influence their Xanthine Oxidase Inhibition Using Discriminant Analysis

Abstract

Background: Hyperuricemia, a condition characterized by elevated uric acid in the blood, is the underlying
cause of gout and oxidative stress, which is also linked to carcinogenesis, atherosclerosis, and inflammation. The management of hyperuricemia mainly relies upon the use of xanthine oxidase (XO) inhibitors. However, the unpleasant side effects of drugs for hyperuricemia has spurred the discovery and development of new classes of compounds with XO inhibitory action.

Objective and Methodology: In this work, 20 QSAR descriptors were generated for each compound in a
dataset consisting of 73 XO inhibitors with a wide range of IC50 values. Principal Component Analysis (PCA) and Discriminant Analysis (DA) were employed to unveil the key QSAR properties of the polyaryl compounds that influence the observed XO inhibitory activity.

Results and Conclusion: Discriminant analysis resulted in a four-descriptor linear function that correctly
classified polyaryl compounds as active or inactive with 85% accuracy. In particular, it suggests that ovality,
absolute hardness, minimum value of localized ionization potential, and number of hydrogen bond acceptors
are the key predictors that determine the XO inhibitory activity of polyaryls. Further, the results suggest that a more spherical and less ionizable molecule, with more diffused electron density and fewer H-bond acceptors than the present polyaryls, promises to be a more active drug for gout.