Structural features of guinea pig aldehyde oxidase inhibitory activities of flavonoids explored using QSAR and molecular modeling studies

In this study, guinea pig aldehyde oxidase inhibitory activities of flavonoids were investigated using in silico, quantitative structure–activity relationships, molecular modeling, and experimental techniques, in order to understand more about their mode of interactions. The aldehyde oxidase inhibitory activity values determined experimentally in this work or collected from our previous report were used to derive mathematical models for the prediction purposes employing combined genetic algorithm and partial least square method, as well as multiple linear regression analysis. The statistical parameters for the developed models and the results of leave-one-out internal cross-validation were indicative of the validity of the models. To further investigate the mechanism of interaction between flavonoid inhibitors and guinea pig aldehyde oxidase enzyme, the structural model of the enzyme was built and the inhibitors were docked manually into the binding site. The model for quercetin-aldehyde oxidase complex was validated based on its appropriate stability during 10 ns molecular dynamics simulation, and hence the positioning procedure for the rest of flavonoids was guided based on the manually docked position of quercetin. The identified interactions were compared with those of flavonoids previously reported for rat aldehyde oxidase and the results showed a substantial commonality between the modes of interactions predicted for flavonoids positioned into the binding site of aldehyde oxidase from guinea pig and rat. This commonality is also reflected by the quantitative structure–activity relationships models. The results presented in this work may provide useful information where the structural requirements for aldehyde oxidase inhibition are sought, such as designing novel aldehyde oxidase inhibitors or investigating drug interaction involving aldehyde oxidase mediated biotransformation.