Rhamnocitrin isolated from Prunus padus var. seoulensis: A potent and selective reversible inhibitor of human monoamine oxidase A

Abstract

Three flavanones and two flavones were isolated from the leaves of Prunus padus var. seoulensis by the activity-guided screening for new monoamine oxidase (MAO) inhibitors. Among the compounds isolated, rhamnocitrin (5) was found to potently and selectively inhibit human MAO-A (hMAO-A, IC50=0.051 μM) and effectively inhibit hMAO-B (IC50=2.97 μM). The IC50 value of 5 for hMAO-A was the lowest amongst all natural flavonoids reported to date, and the potency was 20.2 times higher than that of toloxatone (1.03 μM), a marketed drug. In addition, 5 reversibly and competitively inhibited hMAO-A and hMAO-B with Ki values of 0.030 and 0.91 μM, respectively. Genkwanin (4) was also observed to strongly inhibit hMAO-A and hMAO-B (IC50=0.14 and 0.35 μM, respectively), and competitively inhibit hMAO-A and hMAO-B (Ki=0.097 and 0.12 μM, respectively). Molecular docking simulation reveals that the binding affinity of 5 with hMAO-A (-18.49 kcal/mol) is higher than that observed with hMAO-B (0.19 kcal/mol). Compound 5 interacts with hMAO-A at four possible residues (Asn181, Gln215, Thr336, and Tyr444), while hMAO-B forms a single hydrogen bond at Glu84. These findings suggest that compound 5 as well as 4 can be considered as novel potent and reversible hMAO-A and/or hMAO-B inhibitors or useful lead compounds for future development of hMAO inhibitors in neurological disorder therapies.