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QSAR study of flavonoids’ immunomodulatory activity

Flavonoids are a group of phytochemicals ubiquitous in photosynthesizing organisms that display a remarkable array of biochemical and pharmacological activities. As human immune system can be modified by diet, pharmacologic agents, environmental pollutants, it is assumed that certain members of this group of compounds significantly affect the function of the immune system. Using appropriate cell culture model (human macrophage-like cells - differentiated THP-1 cells), the effects of 31 flavonoid representative on the production of selected cytokines that play crucial roles in innate and adaptive immune responses was determined (TNFα , IL-1β ) [1]. TNFα and IL-1β production was measured using ELISA 24 hrs after the addition of chosen flavonoids in 30 μ M concentration. E. coli lipopolysacharide was used as a positive control (TNFα and IL-1β production was considered as maximal, 100%). Un-stimulated cells did not produce cytokines and were used as a negative control. Some of tested flavonoids exhibited immunomodulatory effects and quantitative structure-activity relationships could be established. 26 Mulliken charges and sums there of corresponding to selected substituents were calculated based on B3LYP DFT single point approach. PM3 optimized geometries were used for these calculations. Random forests (RF) and genetic algorithms coupled with support vector machines (GA/SVM) were used for the development of quantitative relationships between percentages of activation of TNFα and IL-1β production and selected partial atomic charges. RF parameters were kept at their default values while GA/SVM parameters were fine-tuned by internal leave-one-out validation loop. Models obtained this way were characterized by average R2 greater than 0.65 for calculated and experimental values while corresponding CV was less than 5%. These values were calculated based on external leave-one-out validation approach repeated ten times for different random seeds. Descriptors highly ranked by both, RF and GA/SVM approaches were extracted and their influence, as well as the influence of different substituents on the TNFα and IL-1β production was evaluated.

QSAR; flavonoids; immunomodulatory activity

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