Osthenol,a prenylated coumarin,as a monoamine oxidase A inhibitor with high selectivity |
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Authors: | Seung Cheol Baek Myung-Gyun Kang Ji-Eun Park Jae Pil Lee Hanna Lee Hyung Won Ryu Chul Min Park Daeui Park Myoung-Lae Cho Sei-Ryang Oh Hoon Kim |
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Affiliation: | 1. Department of Pharmacy and Research Institute of Life Pharmaceutical Sciences, Sunchon National University, Suncheon 57922, Republic of Korea;2. Department of Predictive Toxicology, Korea Institute of Toxicology, Daejeon 34114, Republic of Korea;3. National Development Institute of Korean Medicine, Gyeongsan 38540, Republic of Korea;4. Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, 30 Yeongudanji-ro, Ochang-eup, Cheongju, Chungbuk 28116, Republic of Korea;5. Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea |
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Abstract: | Osthenol (6), a prenylated coumarin isolated from the dried roots of Angelica pubescens, potently and selectively inhibited recombinant human monoamine oxidase-A (hMAO-A) with an IC50 value of 0.74?µM and showed a high selectivity index (SI?>?81.1) for hMAO-A versus hMAO-B. Compound 6 was a reversible competitive hMAO-A inhibitor (Ki?=?0.26?µM) with a potency greater than toloxatone (IC50?=?0.93?µM), a marketed drug. Isopsoralen (3) and bakuchicin (1), furanocoumarin derivatives isolated from Psoralea corylifolia L., showed slightly higher IC50 values (0.88 and 1.78?µM, respectively) for hMAO-A than 6, but had low SI values (3.1 for both). Other coumarins tested did not effectively inhibit hMAO-A or hMAO-B. A structural comparison suggested that the 8-(3,3-dimethylallyl) group of 6 increased its inhibitory activity against hMAO-A compared with the 6-methoxy group of scopoletin (4). Molecular docking simulations revealed that the binding affinity of 6 for hMAO-A (?8.5?kcal/mol) was greater than that for hMAO-B (?5.6?kcal/mol) and that of 4 for hMAO-A (?7.3?kcal/mol). Docking simulations also implied that 6 interacted with hMAO-A at Phe208 and with hMAO-B at Ile199 by carbon hydrogen bondings. Our findings suggest that osthenol, derived from natural products, is a selective and potent reversible inhibitor of MAO-A, and can be regarded a potential lead compound for the design of novel reversible MAO-A inhibitors. |
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Keywords: | Osthenol Human monoamine oxidase A Selective competitive inhibitor Molecular docking |
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