Improved quantitative structure-activity relationship models to predict antioxidant activity of flavonoids in chemical, enzymatic, and cellular systems

Abstract

Quantitative structure-activity relationship (QSAR) models are useful in understanding how chemical structure relates to the biological activity of natural and synthetic chemicals and for design of newer and better therapeutics. In the present study, 46 flavonoids and related polyphenols were evaluated for direct/indirect antioxidant activity in three different assay systems of increasing complexity (chemical, enzymatic, and intact phagocytes). Based on these data, two different QSAR models were developed using (i) physicochemical and structural (PC&S) descriptors to generate multiparameter partial least squares (PLS) regression equations derived from optimized molecular structures of the tested compounds and (ii) a partial 3D comparison of the 46 compounds with local fingerprints obtained from fragments of the molecules by the frontal polygon (FP) method. We obtained much higher QSAR correlation coefficients (r) for flavonoid end-point antioxidant activity in all three assay systems using the FP method (0.966, 0.948, and 0.965 for datasets evaluated in the biochemical, enzymatic, and whole cell assay systems, respectively). Furthermore, high leave-one-out cross-validation coefficients (q2) of 0.907, 0.821, and 0.897 for these datasets, respectively, indicated enhanced predictive ability and robustness of the model. Using the FP method, structural fragments (submolecules) responsible for the end-point antioxidant activity in the three assay systems were also identified. To our knowledge, this is the first QSAR model derived for description of flavonoid direct/indirect antioxidant effects in a cellular system, and this model could form the basis for further drug development of flavonoid-like antioxidant compounds with therapeutic potential.

Figure 1

Correlation of end-point antioxidant activity in the DPPH, X/XO, and BM phagocyte assay systems. Panels A and B: Plots of polyphenol DPPH radical scavenging activity vs antioxidant effects in the X/XO system. Panels C and D: Plots of polyphenol DPPH radical scavenging activity vs antioxidant effects in the in BM cell system. Activities are represented as logarithm (logIC₂₅) (A and C) and inverse (1/IC₂₅) values (B and D). Compounds 6 and 18 were omitted from the regression calculation in panel A and are shown as outliers.

Figure 2

Comparison of calculated and experimentally-determined antioxidant activities for flavonoids and related polyphenols in the DPPH, X/XO, and BM phagocyte assay systems. QSAR analysis was performed using physicochemical and structural (PC&S) descriptors (left panels) and the FP method (right panels).

Figure 3

Correlation coefficient determined for the PLS-derived QSAR models after exclusion of individual PC&S descriptors. The indicated descriptor under each bar was excluded, and the resulting r values are shown.

Figure 4

Illustration of molecule subdivision into fragments for QSAR analysis. Subdivision of compounds 32 and 42 into rigid (enclosed by dashed lines) and flexible fragments is shown.