Lee Hyun Woo, Ryu Hyung Won, Kang Myung-Gyun, Park Daeui, Oh Sei-Ryang, Kim Hoon
Department of Pharmacy and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea.
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongju, Chungbuk 28116, Republic of Korea.
Bioorg Med Chem Lett. 2017 Mar 1;27(5):1136-1140. doi: 10.1016/j.bmcl.2017.01.085. Epub 2017 Jan 31.
Monoamine oxidase (MAO) catalyzes the oxidation of monoamines that act as neurotransmitters. During a target-based screening of natural products using two isoforms of recombinant human MAO-A and MAO-B, purpurin (an anthraquinone derivative) was found to potently and selectively inhibit MAO-A, with an IC value of 2.50μM, and not to inhibit MAO-B. Alizarin (also an anthraquinone) inhibited MAO-A less potently with an IC value of 30.1μM. Furthermore, purpurin was a reversible and competitive inhibitor of MAO-A with a K value of 0.422μM. A comparison of their chemical structures suggested the 4-hydroxy group of purpurin might play an important role in its inhibition of MAO-A. Molecular docking simulation showed that the binding affinity of purpurin for MAO-A (-40.0kcal/mol) was higher than its affinity for MAO-B (-33.9kcal/mol), and that Ile 207 and Gly 443 of MAO-A were key residues for hydrogen bonding with purpurin. The findings of this study suggest purpurin is a potent, selective, reversible inhibitor of MAO-A, and that it be considered a new potential lead compound for development of novel reversible inhibitors of MAO-A (RIMAs).
单胺氧化酶（MAO）催化作为神经递质的单胺的氧化反应。在使用重组人MAO-A和MAO-B的两种同工型对天然产物进行基于靶点的筛选过程中，发现紫红素（一种蒽醌衍生物）能有效且选择性地抑制MAO-A，IC值为2.50μM，而不抑制MAO-B。茜素（也是一种蒽醌）对MAO-A的抑制作用较弱，IC值为30.1μM。此外，紫红素是MAO-A的可逆竞争性抑制剂，K值为0.422μM。对它们化学结构的比较表明，紫红素的4-羟基可能在其对MAO-A的抑制中起重要作用。分子对接模拟显示，紫红素与MAO-A的结合亲和力（-40.0kcal/mol）高于其与MAO-B的亲和力（-33.9kcal/mol），并且MAO-A的Ile 207和Gly 443是与紫红素形成氢键的关键残基。本研究结果表明，紫红素是一种有效的、选择性的、可逆的MAO-A抑制剂，可被视为开发新型MAO-A可逆抑制剂（RIMAs）的新的潜在先导化合物。
