Selective Interactions of -Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B.

A set of structurally related -methylated flavonoid natural products isolated from (), ( and ), (), (), and () plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds , , and showed selective inhibition of MAO-A, while and showed selective inhibition of MAO-B. Compound showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds - and with MAO-A, and compounds and with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by and , while a partially-reversible mixed-type inhibition by . Similarly, enzyme inhibition-kinetics analysis with compounds , , and , suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the -methylated flavonoids ( and -) and chalcones ( and ) to MAO-A matched closely with the trend in the experimental ICs. Analysis of the binding free-energies suggested better interaction of and with MAO-B than with MAO-A. The natural -methylated flavonoid () with highly potent inhibition (IC 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders.