Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B

doi:10.1016/j.bmc.2005.05.071

CORC > 昆明植物研究所 > 中国科学院昆明植物研究所 > 植物化学与西部植物资源持续利用国家重点实验室

	Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B
	Pan, WL ; Tan, NH ; Zeng, GZ ; Zhang, YM ; Jia, RR
刊名	BIOORGANIC & MEDICINAL CHEMISTRY
	2005-10-15
卷号	13 期号:20 页码:5819-5825
关键词	Cathepsin b Amentoflavone Flexx Docking Qsar
ISSN号	0968-0896
DOI	10.1016/j.bmc.2005.05.071
文献子类	Article
英文摘要	Cathepsin B (CatB) is a member of the papain superfamily of cysteine proteases and has been implicated in the pathology of numerous diseases, including arthritis and cancer. Amentoflavone is found in a number of plants with medicinal properties, including Ginkgo biloba and Hypericum perforatum (St. John's Wort). Herein, we report the structure-activity relationship (SAR) and binding mechanism of three biflavones, amentotlavone (AMFl), 4"'-methylamentoflavone (AMF2) and 7",4"'- dimethy-lamentoflavone (AMF3), isolated from Taxodium mucronatum by us as novel natural inhibitors of human CatB with strong inhibitory activities at IC50 values of 1.75, 1.68 and 0.55 mu M, respectively. Density functional theory (DFT) method was applied to optimize the geometry structures of AMFl, AMF2 and AMF3 at the B3LYP/6-31G* level. FlexX was explored to dock the three biflavones to the binding sites of CatB, and to get a better understanding of vital interactions between these biflavones and CatB. A good correlation between the calculated quantum descriptors and the experimental inhibitory activities suggested that quantum model of these potential inhibitors is reliable. Through geometry and electron structure analysis of AMFs, it was observed that the CH3 substitute at 7" and 4 positions could not vary the difference in geometry structure significantly, but increase the electron density of A-ring, HOMO energy, hydrophobic property, and improve inhibitory activity. Structural and energetic analysis of AMFs and AMFs-CatB complexes showed that the electron-donor site is the A-ring, which shows the highest HOMO energy distribution, and the electron-acceptor site is the F-ring, which shows the highest LUMO energy distribution in AMFs, and the pi-pi interaction between A-ring and residue Trp221, two hydrogen bonds (O5 and Trp221; O4 and Gln23), hydrophobic interaction between the C-ring and residue Cys29 and CH3 substitutes at 7" and 4 might play a crucial role in the inhibition of AMFs on CatB. Results indicated that AMFs are new natural reversible inhibitors that would be useful in developing potent inhibitors of CatB. (c) 2005 Elsevier Ltd. All rights reserved.
学科主题	Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic
WOS关键词	PROTEIN-LIGAND INTERACTIONS ; DENSITY-FUNCTIONAL THEORY ; SCORING FUNCTION ; CRYSTAL-STRUCTURE ; FLEXIBLE DOCKING ; ALGORITHM
WOS研究方向	Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种	英语
WOS记录号	WOS:000231933200016
公开日期	2012-03-21
内容类型	期刊论文
源URL	[http://ir.kib.ac.cn:8080/handle/151853/4152]
专题	昆明植物研究所_植物化学与西部植物资源持续利用国家重点实验室
作者单位	1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources, Kunming 650204, Peoples R China 2.Chinese Acad Sci, Grad Sch, Beijing 100039, Peoples R China
推荐引用方式 GB/T 7714	Pan, WL,Tan, NH,Zeng, GZ,et al. Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2005,13(20):5819-5825.
APA	Pan, WL,Tan, NH,Zeng, GZ,Zhang, YM,&Jia, RR.(2005).Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B.BIOORGANIC & MEDICINAL CHEMISTRY,13(20),5819-5825.
MLA	Pan, WL,et al."Amentoflavone and its derivatives as novel natural inhibitors of human Cathepsin B".BIOORGANIC & MEDICINAL CHEMISTRY 13.20(2005):5819-5825.