tailieunhanh - Báo cáo khoa học: Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 (AriceptÒ) to cholinesterases

E2020 (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl)piperidine hydrochloride isa piperidine-based ace-tylcholinesterase (AChE) inhibitor that was approved for the treatment of Alzheimer’s disease in the United States. Structure-activity studiesof thisclassof inhibitorshave indicated that both the benzoyl containing functionality and the N-benzylpiperidine moiety are the key featuresfor binding and inhibition of AChE. | Eur. J. Biochem. 270 4447-4458 2003 FEBS 2003 doi Aromatic amino-acid residues at the active and peripheral anionic sites control the binding of E2020 Aricept to cholinesterases Ashima Saxena1 James M. Fedorko1 C. R. Vinayaka1 Rohit Medhekar2 Zoran Radic3 Palmer Tavlor3 . . . Oksana Lockridge4 and Bhupendra P. Doctor1 1 Division of Biochemistry Walter Reed Army Institute of Research Silver Spring MD USA department of Chemistry University of California Davis CA USA 3 University of California San Diego La Jolla CA USA 4Eppley Cancer Institute University of Nebraska Medical Center Omaha NE USA E2020 R S -1-benzyl-4- 5 6-dimethoxy-1-indanon -2-yl -methyl piperidine hydrochloride is a piperidine-besed acetylcholinesterase AChE inhibitor that was approved for the treatment of Alzheimer s disease in the United States. Structure-activity stsrees of Ulis clais of inliih ivirs have indicated that both the benzoyl containing functionality and the N-benzylpiperidine moiety are the key features for binding and inhibition of AChE. In the present study the interaction of E2020 with cholinesterases ChEs with known sequence differences was examined in more detail by measuring the inhibition constants with Torpedo AChE fetal bovine serum AChE human butyrylcholinesterase BChE and equine BChE. The basis for particular residues conferring selectivity was then confirmed by using sitespecific mutants of the implicated residue in two template enzymes. Differences in the reactivity of E2020 toward AChE and BChE 200- to 400-fold show that residues at the peripheral anionic site such as Asp74 72 Tyr72 70 Tyr124 121 and Top286 279 in mammalian AChE may be important in the binding of E2020 to AChE. Site-directed mutagenesis studies using mouse AChE showed that these residues contribute to the stabilization energy for the AChE-E2020 complex. However replacement of A1s277 Top279 with Trp in human BChE doesnot affect the binding of E2020 to BChE. Molecular .

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