Selective inhibition of monoamine oxidase A by chelerythrine, an isoquinoline alkaloid

Chelerythrine, an isoquinoline alkaloid isolated from the herbaceous perennial Chelidonium majus, was found to potently and selectively inhibit an isoform of recombinant human monoamine oxidase-A (MAO-A) with an IC50 value of 0.55 mu M. Chelerythrine was a reversible competitive MAO-A inhibitor (K-i=0.22 mu M) with a potency much greater than toloxatone (IC50=1.10 mu M), a marketed drug. Other isoquinoline alkaloids tested did not effectively inhibit MAO-A or MAO-B. A structural comparison with corynoline suggested the 1-and/or 2-methoxy groups of chelerythrine increase its inhibitory activity against MAO-A. Molecular docking simulations revealed that the binding affinity of chelerythrine for MAO-A (-9.7 kcal/mol) was greater than that for MAO-B (-4.6 kcal/mol). Docking simulation implied that Cys323 and Tyr444 of MAO-A are key residues for hydrogenbond interaction with chelerythrine. Our findings suggest chelerythrine is one of the most reversible selective and potent natural inhibitor of MAO-A, and that it be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors.