engleski

Structural and electronic features responsible for antiaggregatory effect of flavonoids

Leading causes of death in developed countries are cardiovascular diseases. Polyphenols, namely flavonoids and phenolic acids, have many pharmacological properties that can explain their protective role in the prevention of cardiovascular diseases: antioxidant capacity, vasorelaxation, anti-inflammatory and antiaggregatory effects. Benfitial effects of natural sources of polyphenolics on platelet aggregation souch as wine (Franch paradox), green tea (Asian paradox), dark chocolate, gingko, propolis are well documented. The goal of this work is to determine molecular descriptors responsible for antiaggregatory effect of flavonoids based on the set of thirty flavonoids. The biological end point was defined as minimal concentration of flavonoid that can lower the platelet aggregation statistically compared to the negative control. Measurements were done on the whole blood using Multiplate® (multiple platelet functional analyzer) and adenosine diphosphate as weak agonist of aggregation (ADP test). Molecular descriptors were generated using MOPAC 7 (Stewart Computational Chemistry, USA), ACD/ChemSketch Freeware (Advanced Chemistry Development, USA), ChemFileBrowser (Hyleos, USA) and TAM (Faculty of Pharmacy and Biochemistry, Croatia). These included: steric (molecular weight, volume, area), hydrophobic parameters (Hansch’s parameter), molar refraction and electronic parameters (total energy, HOMO, LUMO, dipole moment, partial charges, bond orders). Statistical analysis was done in Statistica v7.1 while prediction, based on random forests and leave-one-out external validation, has been made within R v2.8.1 environment. Preliminary results suggest Mulliken’s partial atom charge and substituent charge as the most important molecular features for modeling of antiaggregatory effects of selected flavonoids. The determination of structural and electronic features responsible for antiaggregatory efficacy of flavonoids will provide basis for either synthesis of new flavonoids or selection of potent flavonoids from natural sources.

antiaggregatory effect; flavonoids; QSAR

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