Density functional theory (DFT) and linear regression analysis method are used to investigate the quantitative structure-activity relationship (QSAR) and structural modification for the inhibition of MMP-9 by flavonoids. It is found that there are good linear relationships between the experimental biological activity data (－lg EC₅₀) for the inhibition of MMP-9 by flavonoids and the calculated lowest unoccupied molecular orbital energies and the molecular hydration energies of flavonoids. The results from leave-one-out cross-validation show that the established two QSAR models have good stability and prediction ability. Further studies indicate that the biological activities for the modified molecules on MMP-9 inhibition can be improved, when the structural modifications are carried out on the suitable positions of A ring, B ring and C ring of flavonoid molecules using the substituent groups that have the strong electron-donating ability and can lower the molecular hydration energies of flavonoids. According to the results (33 compounds) obtained from the structural modifications for the luteolin molecule, we suggest the possible mechanisms for the inhibition of MMP-9 by flavonoids, and design the eight MMP-9 inhibitors whose biological activities are obviously improved by the structural modifications, which are expected to be confirmed experimentally.

Key words: flavonoids, MMP-9, QSAR, structural modification, DFT, linear regression analysis, biological activity