Potent selective monoamine oxidase B inhibition by maackiain, a pterocarpan from the roots of Sophora flavescens = 고삼에서 pterocarpan인 maackiain에 의한 강력한 선택적 모노아민산화 효소 B의 저해

Abstract

Monoamine oxidase (MAO) catalyzes the oxidation of monoamines and its two isoforms, MAO-A and MAO-B, break down neurotransmitter amines. Of the compounds isolated from the roots of Sophora flavescens, (-)-maackiain (4), a pterocarpan, was found to potently and selectively inhibit human MAO-B, with an IC50 of 0.68 μM, and to have a selectivity index of 126.2 for MAO-B. As compared with other herbal natural products, the IC50 value of 4 for MAO-B is one of the lowest reported to date. Genistein (1) highly, effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 3.9 μM and 4.1 μM, respectively. (-)-4-Hydroxy-3-methoxy-8,9-methylenedioxypterocarpan (2) effectively and non-selectively inhibited MAO-A and MAO-B with IC50 values of 20.3 μM and 10.3 μM, respectively. In addition, compound 4 reversibly and competitively inhibited MAO-B with a Ki value of 0.054 μM. Molecular docking simulation revealed that the binding affinity of 4 for MAO-B (-26.6 kcal/mol) was greater than its affinity for MAO-A (-8.3 kcal/mol), which was in-line with our inhibitory activity findings. Furthermore, Cys172 of MAO-B was found to be a key residue for hydrogen bonding with compound 4. The findings of this study suggest compound 4 be viewed as a new potent, selective, and reversible MAO-B inhibitor, and that compounds 1 and 2 be considered useful lead compounds for the developments of nonselective and reversible MAO inhibitors for the treatment of disorders like Parkinson's disease, Alzheimer disease, and depression.