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| - | ==AChE monovalent inhibitors (continuation of the page [[AChE inhibitors and substrates]])==
| + | #REDIRECT [[AChE_inhibitors_and_substrates#Treatment_of_Alzheimer.27s_disease]] |
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| - | <applet load='2ack' size='500' frame='true' align='left'
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| - | scene='2ack/Com_view/1' />
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| - | '''6) Edrophonium (EDR)''' ([[2ack]]) is stacked between the aromatic rings of <scene name='2ack/Com_view/2'>W84 and F330</scene>, near the ''Tc''AChE <scene name='2ack/Com_view/3'>catalytic triad</scene> which consists of '''S200''', '''E327''', and '''H440'''.
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| - | <applet load='1gqr' size='500' frame='true' align='right'
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| - | scene='1gqr/Com_view/1' />
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| - | '''7) Rivastigmine (Exelon)''' is a carbamate inhibitor of AChE, and it is currenly used in therapy of Alzheimer's disease. Rivastigmine (colored yellow) interacts with ''Tc''AChE <font color='lime'><b>(colored lime)</b></font> at the <scene name='1gqr/Active_site/4'>active-site gorge</scene>. The carbamyl moiety of rivastigmine is <scene name='1gqr/Active_site/9'>covalently bound</scene> to the active-site S200 Oγ. The second part of rivastigmine (the leaving group), NAP ((−)-S-3-[1-(dimethylamino)ethyl]phenol) is also held in the active-site gorge, but it is <scene name='1gqr/Active_site/6'>separated</scene> from the carbamyl moiety, hence, carbamylation took place. The <scene name='1gqr/Active_site/7'>crystal structure</scene> of ''Tc''AChE/<font color='magenta'><b>NAP (colored magenta)</b></font> is known ([[1gqs]]). The <font color='violet'><b>''Tc''AChE active-site residues</b></font> which are interacting with NAP are <font color='violet'><b>colored violet</b></font>. NAP is located in a similar region of ''Tc''AChE active site, but with different orientation than that of the NAP part (colored yellow) in the ''Tc''AChE/rivastigmine complex. Only H440 and F330 significantly change their side-chain conformations. <scene name='1gqr/Active_site/8'>Overlap</scene> of the ''Tc''AChE active sites in 4 different structures (<font color='lime'><b>''Tc''AChE</b></font>/rivastigmine, <font color='violet'><b>''Tc''AChE</b></font>/<font color='magenta'><b>NAP</b></font>, <font color='cyan'><b>native ''Tc''AChE</b></font>([[2ace]]), and ''Tc''AChE/'''VX''' ([[1vxr]], ''Tc''AChE colored white and VX black)) reveals that the conformation of H440 in the ''Tc''AChE/NAP structure is very similar its conformation in the native ''Tc''AChE ([[2ace]]), but the distance between H440 Nδ and E327 Oε is significantly longer in the ''Tc''AChE/rivastigmine and the ''Tc''AChE/'''VX''' complexes. This structural change disrupts the catalytic triad consisting of S200, E327, H440. This could explain the very slow kinetics of AChE reactivation after its inhibition by rivastigmine.
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| - | <applet load='AC5.pdb' size='500' frame='true' align='left'
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| - | scene='2j3q/Active_site/1' />
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| - | '''8)''' The ''Tc''AChE active site consists of two binding subsites. One of them is the "catalytic anionic site" (CAS), which involves the catalytic triad <scene name='2j3q/Active_site/2'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the conserved residues <scene name='2j3q/Active_site/3'>Trp84 and Phe330</scene> which also participate in ligand recognition. Another conserved residue <scene name='2j3q/Active_site/4'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> is situated at the second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. <scene name='2j3q/Active_site/6'>Thioflavin T</scene> is a good example of the PAS-binding AChE inhibitors. <scene name='2j3q/Active_site/7'>Superposition</scene> of the crystal structure of the <font color='red'><b>edrophonium </b></font>/''Tc''AChE (mentioned above as a CAS-binding inhibitor) ([[2ack]]) on the <font color='magenta'><b>thioflavin T</b></font> /''Tc''AChE complex structure ([[2j3q]]) shows that these ligands' positions do not overlap. Of note is that Phe330, which is part of the CAS, is the single residue interacting with <font color='magenta'><b>thioflavin T</b></font>. This residue is the only one which significantly <scene name='2j3q/Active_site/8'>changes its conformation</scene> to avoid clashes in comparison to other CAS residues of the <font color='red'><b>edrophonium </b></font>/''Tc''AChE complex.
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| - | <applet load='AC1.pdb' size='500' frame='true' align='right'
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| - | scene='2vja/Common/1' />
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| - | '''9)''' <scene name='2vja/Common/3'>OTMA</scene> is a nonhydrolyzable substrate analogue of AChE. Its hydrolysis is impossible as OTMA possesses <scene name='2vja/Common/4'>carbon</scene> atom instead of the <scene name='2vja/Common/5'>ester oxygen</scene> in the AChE natural substrate ACh. Similarly to ACh, OTMA covalently binds to the ''Tc''AChE ([[2vja]]) <scene name='2vja/Active_site/1'>Ser200</scene> Oγ at the CAS. At this subsite OTMA also interacts with <scene name='2vja/Active_site/2'>Trp84, Phe330</scene> (cation-π interactions); <scene name='2vja/Active_site/3'>Glu199</scene> (electrostatic interaction); <scene name='2vja/Active_site/4'>Gly118, Gly119, and Ala201</scene>(hydrogen bonds). OTMA binds not only at CAS, but also at PAS. A second OTMA molecule interacts with <scene name='2vja/Active_site/5'>Trp279, Tyr70</scene> (cation-π interactions), and <scene name='2vja/Active_site/6'>Tyr121</scene> (weak hydrogen bond). Thus, this dual binding mode of OTMA with ''Tc''AChE (to CAS and PAS) could be prototypical for [[AChE bivalent inhibitors]].
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| - | '''Please see also our pages [[AChE bivalent inhibitors]] and [[AChE bivalent inhibitors (Part II)]].'''
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| - | ==Selected 3D Structures of AChE ==
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| - | * [[2ace]] This is the original solved structure for '''Torpedo Californica'''
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| - | * [[1ea5]] This is one of the highest quality representative X-ray structures in the PDB.
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| - | * [[1eve]] The E2020 (Aricept) complex.
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| - | * [[1ax9]] Endrophonium complex.
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| - | * [[1vot]] Complex with Huperzine, a Chinese folk medicine.
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| - | * [[1fss]] Complex with snake venum toxin Fasciculin-II.
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| - | * [[1acj]] Complex with tacrine.
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| - | * [[1e66]] Complex with huprine X.
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| - | * [[1dx6]] Complex with galanthamine.
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| - | * [[1w6r]] Complex with galanthamine iminium derivative.
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| - | * [[2ack]] Complex with edrophonium.
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| - | * [[1vzj]] Structure of the tetramerization domain of acetylcholinesterase.
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| - | * [[1gqr]] Complex with rivastigmine.
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| - | * [[1gqs]] Complex with NAP alone.
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| - | * [[1vxr]] Complex with VX.
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| - | * [[2vja]] Complex with OTMA.
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| - | ==References==
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| - | <ref group='xtra'>PMID:8989325</ref> <ref group='xtra'>PMID:8415649</ref><ref group='xtra'>PMID:15563167</ref><ref group='xtra'>PMID:10089512</ref><ref group='xtra'>PMID:16076210</ref> <ref group='xtra'>PMID:10476864</ref><ref group='xtra'>PMID:12517147</ref><ref group='xtra'>PMID:1678899</ref><ref group='xtra'>PMID:10606746</ref><ref group='xtra'>PMID:11888271</ref><ref group='xtra'>PMID:18701720</ref> <ref group='xtra'>PMID:11863435</ref><ref group='xtra'>PMID:18512913</ref>
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| - | <references group='xtra'/>
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| - | [[Category: catalytic triad]]
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| - | [[Category: Cholinesterase]]
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| - | [[Category: Acetylcholinesterase]]
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| - | [[Category: AChE inhibitors]]
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| - | [[Category: inhibitor]]
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| - | [[Category: cholinesterases]]
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| - | [[Category: acetylcholine]]
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| - | [[Category: cation-pi]]
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| - | [[Category: Alzheimer's disease]]
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