Revealing the role of fluorine pharmacophore in chalcone scaffold for shifting the MAO-B selectivity: investigation of a detailed molecular dynamics and quantum chemical study

The development of highly selective monoamine oxidase-B (MAO-B) inhibitors has great therapeutic benefit in treatment of various neurodegenerative disorders. Recent study documented that shifting of fluorine atom fromparatoorthoposition on the phenyl B ring of heteroaryl chalcones shown a remarkable shift in the selectivity and potency between MAO-A and MAO-B isoforms. Despite the large plethora of the design of new selective MAO-B inhibitors, the current paper illustrates the role and orientation of fluorine atom with remarkable MAO-B selectivity of three compounds (O23, O24 and O25), which differ from all other substituents encountered in the chalcone scaffolds is recently reported by our group. Conformational analyses of differential inhibitory effects of O23, O24 and O25 on MAO-A and MAO-B, differential analyses of complementary interactions at MAO-A/-B active sites and differential analysis of affinity binding and per-residue energy contributions are calculated by molecular dynamics study. Density functional theory based electronic structure calculations were employed with special emphasis to electrostatic potential and frontier molecular orbitals. Results of the current study can be used for lead modification and a new insight for the development of novel fluorinated chalcones for the treatment of various neurodegenerative disorders. Communicated by Ramaswamy H. Sarma

Automated summary

The development of highly selective monoamine oxidase-B (MAO-B) inhibitors has shown great therapeutic potential in treating various neurodegenerative disorders. Recent research has highlighted the significant impact of the position and orientation of fluorine atoms on the selectivity of three compounds in MAO-B inhibition, providing a novel direction for the development of fluorinated chalcones for neurodegenerative disorder treatment.