Monoamine Oxidase Inhibition of Butyrolactone I from Marine Aspergillus terreus and Virtual Screening of Its Analogs
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摘要: 【目的】为研究海洋土曲霉（Aspergillus terreus）C23-3的次级代谢产物中的单胺氧化酶抑制剂及其抑制作用类型，借助计算机模拟方法探讨同类型化合物对单胺氧化酶的潜在抑制活性及构效关系，以开发单胺氧化酶抑制剂。【方法】采用活性引导下的色谱方法分离纯化得到活性化合物，采用核磁共振、质谱、圆二色谱分析鉴定其结构，采用酶标比色法评价化合物对单胺氧化酶抑制作用。使用Autodock vina对其结构类似物进行抑制单胺氧化酶活性虚拟筛选。【结果】1）分离鉴定得到一个具有单胺氧化酶抑制活性的化合物丁内酯I；2）丁内酯I对单胺氧化酶A和单胺氧化酶B的抑制作用为可逆非竞争性抑制，对单胺氧化酶A的半抑制浓度（IC50）为21.45 μmol/L，抑制常数Ki=6.27 μmol/L；对单胺氧化酶B的IC50为24.16 μmol/L，Ki=12.61 μmol/L；3）分子对接显示丁内酯I可与单胺氧化酶形成多个氢键，五元内酯环为α，γ-二芳基取代、含有苯并吡喃或苯并呋喃基团的aspvinone类丁内酯化合物在虚拟筛选中对单胺氧化酶最小结合亲和力得分更低（即结合力更强）。【结论】丁内酯I是可逆的单胺氧化酶抑制剂，对单胺氧化酶的抑制为非竞争性抑制。真菌来源丁内酯类化合物可作为单胺氧化酶抑制剂的新来源。Abstract: 【Objective】 This study aimed to investigate the monoamine oxidase (MAO) inhibitors from the secondary metabolites of marine Aspergillus terreus C23-3 and their inhibitory types, and investigate the potential MAO inhibitory activity and structure-activity relationship of butyrolactone analogs by computer simulation to develop MAO inhibitors.【Method】 The bioactive compound was obtained by bioactivity-guided chromatographic separation.Its structure was identified by nuclear magnetic resonance spectrometry, mass spectrometry and circular dichroism analyses.The inhibition of the compounds on monoamine oxidase was assayed by colorimetric method in microtiter plates.Autodock vina was used to evaluate the butyrolactone I analogs for monoamine oxidase inhibitory potentials.【Result】 1) An active compound, butyrolactone I, was isolated and identified.2) The inhibitory effect of butyrolactone I on monoamine oxidases A and B was reversible and noncompetitive, the semi-inhibition concentrations (IC50) were 21.45 μmol/L and 24.16 μmol/L respectively, the inhibition constant Ki was 6.27 μmol/L and 12.61 μmol/L respectively.3) Molecular docking showed that butyrolactone I could form multiple hydrogen bonds with amino acid residues of MAOs.Aspvinone-type butyrolactone analogs, which have α, γ-biaryl substituted five-member lactone ring and benzopyran or benzofuran groups, scored lower on the minimal binding affinity with monoamine oxidases in virtual screening.【Conclusion】 Butyrolactone I is a reversible inhibitor of monoamine oxidase, and its inhibition to monoamine oxidase is noncompetitive.Fungal butyrolactones are new source of MAO inhibitors.
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Key words:
- marine fungus /
- secondary metabolites /
- monoamine oxidase /
- inhibition type /
- virtual screening
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TRIPATHI A C, UPADHYAY S, PALIWAL S, et al.Privileged scaffolds as MAO inhibitors:retrospect and prospects[J].European Journal of Medicinal Chemistry, 2018, 145:445-497.
JONES D N, RAGHANTI M A.The role of monoamine oxidase enzymes in the pathophysiology of neurological disorders[J].Journal of Chemical Neuroanatomy, 2021, 114:101957.
SAURA J, NADAL E, VAN DEN BERG B, et al.Localization of monoamine oxidases in human peripheral tissues[J].Life Sciences, 1996, 59(16):1341-1349.
UEHARA S, UNO Y, YAMAZAKI H.Molecular cloning, sequence analysis, and tissue distribution of marmoset monoamine oxidases A and B[J].Drug Metabolism and Pharmacokinetics, 2020, 35(5):479-482.
YANG J M, LIU Y Y, YANG W C, et al.An anti-inflammatory isoflavone from soybean inoculated with a marine fungus Aspergillus terreus C23-3[J].Bioscience, Biotechnology, and Biochemistry, 2020, 84(8):1546-1553.
LIANG J B, YANG Z D, SHU Z M, et al.A rapid thin-layer chromatography bioautographic method for detecting the monoamine oxidase inhibitors in plants[J].Natural Product Research, 2014, 28(17):1318-1321.
HOLT A, SHARMAN D F, BAKER G B, et al.A continuous spectrophotometric assay for monoamine oxidase and related enzymes in tissue homogenates[J].Analytical Biochemistry, 1997, 244(2):384-392.
BEKIRCAN O, DANıŞ Ö, ŞAHIN M E, et al.Monoamine oxidase A and B inhibitory activities of 3, 5-diphenyl-1, 2, 4-triazole substituted[1, 2, 4] triazolo[3, 4-b] [1, 3, 4] thiadiazole derivatives[J].Bioorganic Chemistry, 2022, 118:105493.
ZARMOUH N O, MESSEHA S S, ELSHAMI F M, et al.Evaluation of the isoflavone genistein as reversible human monoamine oxidase-A and -B inhibitor[J].Evidence-Based Complementary and Alternative Medicine, 2016, 2016:1423052.
LEE H W, RYU H W, KANG M G, et al.Potent inhibition of monoamine oxidase A by decursin from Angelica gigas nakai and by wogonin from Scutellaria baicalensis Georgi[J].International Journal of Biological Macromolecules, 2017, 97:598-605.
YANG W C, ZHANG Y Y, LI Y J, et al.Chemical composition and anti-Alzheimer's disease-related activities of a functional oil from the edible seaweed Hizikia fusiforme[J].Chemistry& Biodiversity, 2020, 17(8):e2000055.
BHAWNA, KUMAR A, BHATIA M, et al.Monoamine oxidase inhibitors:A concise review with special emphasis on structure activity relationship studies[J].European Journal of Medicinal Chemistry, 2022, 242:114655.
IBRAHIM S R M, MOHAMED G A, KHEDR A I M.γ-butyrolactones from Aspergillus species:structures, biosynthesis, and biological activities[J].Natural Product Communications, 2017, 12(5):791-800.
MA X H, ZHU T J, GU Q Q, et al.Structures and antiviral activities of butyrolactone derivatives isolated from Aspergillus terreus MXH-23[J].Journal of Ocean University of China, 2014, 13(6):1067-1070.
ZHOU M, DU G, YANG H Y, et al.Antiviral butyrolactones from the endophytic fungus Aspergillus versicolor[J].Planta Medica, 2015, 81(3):235-240.
JALAL K, KHAN K, HALEEM D J, et al.In silico study to identify new monoamine oxidase type a (MAO-A)selective inhibitors from natural source by virtual screening and molecular dynamics simulation[J].Journal of Molecular Structure, 2022, 1254:132244.
EL AISSOUQ A, BOUACHRINE M, OUAMMOU A, et al.Homology modeling, virtual screening, molecular docking, molecular dynamic (MD) simulation, and ADMET approaches for identification of natural anti-Parkinson agents targeting MAO-B protein[J].Neuroscience Letters, 2022, 786:136803.
LEWELLYN K, BIALONSKA D, CHAURASIYA N D, et al.Synthesis and evaluation of aplysinopsin analogs as inhibitors of human monoamine oxidase A and B[J].Bioorganic and Medicinal Chemistry Letters, 2012, 22(15):4926-4929.
DAS T, SAHA S C, SUNITA K, et al.Promising botanicalderived monoamine oxidase(MAO) inhibitors:pharmacological aspects and structure-activity studies[J].South African Journal of Botany, 2022, 146:127-145.
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