首页|High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

High-throughput discovery of highly selective reversible hMAO-B inhibitors based on at-line nanofractionation

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Human monoamine oxidase B(hMAO-B)has emerged as a pivotal therapeutic target for Par-kinson's disease.Due to adverse effects and shortage of commercial drugs,there is a need for novel,high ly selective,and reversible hMAO-B inhibitors with good blood-brain barrier permeability.In this study,a high-throughput at-line nanofractionation screening platform was established with extracts from Chuan-xiong Rhizoma,which resulted in the discovery of 75 active compounds,including phenolic acids,vol atile oils,and phthalides,two of which were highly selective novel natural phthalide hMAO-B inhibitors that were potent,selective,reversible and had good blood-brain permeability.Molecular docking and molecular dynamics simulations elucidated the inhibition mechanism.Sedanolide(IC50=103 nmol/L;SI=645)and neocnidilide(IC50=131 nmol/L;SI=207)demonstrated their excellent potential as hMAO-B inhibitors.They offset the limitations of deactivating enzymes associated with irreversible hMAO-B inhibitors such as rasagiline.In SH-SY5Y cell assays,sedanolide(EC50=0.962 μmol/L)and neocnidilide(EC50=1.161 μmol/L)exhibited significant neuroprotective effects,comparable to the pos-itive drugs rasagiline(EC50=0.896 μmol/L)and safinamide(EC50=1.079 μmol/L).These findings underscore the potential of sedanolide as a novel natural hMAO-B inhibitor that warrants further devel-opment as a promising drug candidate.

Human monoamine oxidase B inhibitorsHigh-throughput screeningAt-line nanofractionationParkinson's diseaseCellular neuroprotectionTraditional Chinese medicines(TCMs)

Yu Fan、Jincai Wang、Jingyi Jian、Yalei Wen、Jiahao Li、Hao Tian、Jacques Crommen、Wei Bi、Tingting Zhang、Zhengjin Jiang

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Institute of Pharmaceutical Analysis/Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research/International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Ministry of Education(MOE)of China/College of Pharmacy,Jinan University,Guangzhou 510632,China

KU Leuven-University of Leuven,Pharmaceutical Analysis,Department of Pharmaceutical and Pharmacological Sciences,Leuven 3000,Belgium

Laboratory of Analytical Pharmaceutical Chemistry,Department of Pharmaceutical Sciences,CIRM,University of Liege,Liege B-4000,Belgium

Department of Neurology,the First Affiliated Hospital of Jinan University/Clinical Neuroscience Institute,the First Affiliated Hospital of Jinan University,Guangzhou 510630,China

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国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金国家自然科学基金中国博士后科学基金中央高校基本科研业务费专项

82073806823044378220434282373835821737812022M72135521623343

2024

10.1016/j.apsb.2024.01.020

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(4)
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