Huperzine A Complexed with Acetylcholinesterase (Chinese): Difference between revisions
New page: left|250px {{STRUCTURE_1vot| PDB=1vot | SCENE= }} '''石杉碱甲与乙酰胆碱酯酶复合物的三维结构''' ==背景介绍== [[Image:HuperzineA3.jpg|left|25... |
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==背景介绍== | ==背景介绍== | ||
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中国科研工作者在20世纪80年代从'''中药'''[http://zh.wikipedia.org/wiki/%E4%B8%AD%E8%8D%AF]千层塔中分离得到天然产物<scene name='1vot/Huperzinea/2'>石杉碱甲</scene>被证实是[[乙酰胆碱酯酶]]的可逆抑制剂，对乙酰胆碱酯酶具有特定、高效的抑制活性。早在1000多年前，中国人已将千层塔用于擦伤、疲惫、肿胀、精神分裂症以及重症肌无力等疾病的治疗。从1996年开始，药品名为双益平[http://www.54md.com/drugstore/pic/gpic_25fd25197010a0fb4a680516735e613c.jpg]的石杉碱甲已在中国广泛用于早老年痴呆症的治疗。与美国食品药品管理局(FDA）批准的目前用于老年痴呆症治疗的多奈哌齐（Donepezil，商品名Aricept）、利伐司替明（Rivastigmine，商品名Exelon）和加兰他敏（Galanthamine，商品名Reminyl）三个药相比，石杉碱甲具有能更好渗透血脑屏障、生物口服利用度更高和对乙酰胆碱酯酶抑制时效更长的特点。 | 中国科研工作者在20世纪80年代从'''中药'''[http://zh.wikipedia.org/wiki/%E4%B8%AD%E8%8D%AF]千层塔中分离得到天然产物<scene name='1vot/Huperzinea/2'>石杉碱甲</scene>被证实是[[乙酰胆碱酯酶]]的可逆抑制剂，对乙酰胆碱酯酶具有特定、高效的抑制活性。早在1000多年前，中国人已将千层塔用于擦伤、疲惫、肿胀、精神分裂症以及重症肌无力等疾病的治疗。从1996年开始，药品名为双益平[http://www.54md.com/drugstore/pic/gpic_25fd25197010a0fb4a680516735e613c.jpg]的石杉碱甲已在中国广泛用于早老年痴呆症的治疗。与美国食品药品管理局(FDA）批准的目前用于老年痴呆症治疗的多奈哌齐（Donepezil，商品名Aricept）、利伐司替明（Rivastigmine，商品名Exelon）和加兰他敏（Galanthamine，商品名Reminyl）三个药相比，石杉碱甲具有能更好渗透血脑屏障、生物口服利用度更高和对乙酰胆碱酯酶抑制时效更长的特点。 | ||
The structure of <scene name='1vot/Huperzinea/2'>HupA</scene> shows some similarity to other known [[AChE inhibitors and substrates]]. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties. | The structure of <scene name='1vot/Huperzinea/2'>HupA</scene> shows some similarity to other known [[AChE inhibitors and substrates]]. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties. | ||
Revision as of 12:59, 5 August 2009
石杉碱甲与乙酰胆碱酯酶复合物的三维结构
背景介绍背景介绍
中国科研工作者在20世纪80年代从中药[1]千层塔中分离得到天然产物被证实是乙酰胆碱酯酶的可逆抑制剂，对乙酰胆碱酯酶具有特定、高效的抑制活性。早在1000多年前，中国人已将千层塔用于擦伤、疲惫、肿胀、精神分裂症以及重症肌无力等疾病的治疗。从1996年开始，药品名为双益平[2]的石杉碱甲已在中国广泛用于早老年痴呆症的治疗。与美国食品药品管理局(FDA）批准的目前用于老年痴呆症治疗的多奈哌齐（Donepezil，商品名Aricept）、利伐司替明（Rivastigmine，商品名Exelon）和加兰他敏（Galanthamine，商品名Reminyl）三个药相比，石杉碱甲具有能更好渗透血脑屏障、生物口服利用度更高和对乙酰胆碱酯酶抑制时效更长的特点。
The structure of shows some similarity to other known AChE inhibitors and substrates. The molecule is fairly rigid and contains an aromatic system as well as a primary amino group that is probably protonated at physiological pH. Various suggestions have been made with respect to its orientation within the active site of AChE, and with respect to the amino acid residue with which its putative pharmacophoric groups might interact. Solution of the 3D structure of a complex of HupA with AChE would permit unequivocal resolution of this issue and it would also provide a rational basis for structure-related drug design aimed at developing synthetic analogues of HupA with improved therapeutic properties.
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三维结构三维结构
The crystal structure of the complex of Torpedo californica AChE (TcAChE) with HupA at 2.5 Å resolution (pdb code 1vot) was determined in 1997 and it shows an unexpected orientation for the inhibitor with surprisingly few strong direct interactions with protein residues to explain its high affinity. The active site of TcAChE was found to be buried at the bottom of a , lined by (colored darkmagenta). The TcAChE natural substrate (ACh) directly binds within the (Ser200, His440, and Glu327). The residues are also important in the ligand recognition. HupA also binds to TcAChE at this active site, but its in comparison to ACh. The principal interactions of are including: a direct through a water molecule as a linker at the bottom of the gorge; cation-pi interactions between the amino group of with the distance between the nitrogen and the centroid of the aromatic rings of 4.8 and 4.7 Å, respectively; at the top of the gorge, HBs through two water molecules as linkers formed between the amino group of . An unusually short (~3.0 Å) C-H→O HB has been seen between the ethylidene methyl group of .
关于此结构关于此结构
1vot is a Single protein structure of sequence from Torpedo californica. Full crystallographic information is available from OCA.
参考文献参考文献
Structure of acetylcholinesterase complexed with the nootropic alkaloid, (-)-huperzine A., Raves ML, Harel M, Pang YP, Silman I, Kozikowski AP, Sussman JL, Nat. Struct. Biol. 1997 Jan;4(1):57-63. PMID:8989325
Huperzine A from Huperzia species-An ethnopharmacolgical review., Ma X, Tan C, Zhu D, Gang D, Xiao P, J. Ethnopharmacol. 2007 Aug;113(1):15-34. PMID:17644292
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