Two dimensional-QSAR and molecular dynamics studies of a selected class of aldoxime- and hydroxy-functionalized chalcones as monoamine oxidase-B inhibitors

Candidates generated from unsaturated ketone (chalcone) demonstrated as strong, reversible and specific monoamine oxidase-B (MAO-B) inhibitory activity. For the research on MAO-B inhibition, our team has synthesized and evaluated a panel of aldoxime-chalcone ethers (ACE) and hydroxylchalcones (HC). The MAO-B inhibitory activity of several candidates is in the micro- to nanomolar range in these series. The purpose of this research was to develop predictive QSAR models and look into the relation between MAO-B inhibition by aldoxime and hydroxyl-functionalized chalcones. It was shown that the molecular descriptors ETA Shape P, MDEO-12, ETA dBetaP, SpMax1 Bhi and ETA EtaP B are significant in the inhibitory action of the MAO-B target. Using the current 2D QSAR models, potential chalcone-based MAO-B inhibitors might be created. The lead molecules were further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex. Communicated by Ramaswamy H. Sarma

Automated summary

This study utilized candidates generated from unsaturated ketone as potent, reversible, and specific MAO-B inhibitors, and identified several compounds with potential MAO-B inhibitory activity in the micro- to nanomolar range through the synthesis and evaluation of aldoxime-chalcone ethers and hydroxylchalcones. Molecular descriptors such as ETA Shape P and MDEO-12 were found to play significant roles in MAO-B inhibition, suggesting the possibility of creating potential chalcone-based MAO-B inhibitors with the current 2D QSAR models. Further analysis of lead molecules was conducted through detailed molecular dynamics study to confirm the stability of the ligand-enzyme complex.