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| - | '''This page is a continuation of the page [[AChE bivalent inhibitors]]'''
| + | #REDIRECT [[AChE inhibitors and substrates]] |
| - | * [[1w4l]] ''Tc''AChE complex with bis-acting galanthamine derivative
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| - | * [[1u65]] ''Tc''AChE complex with anticancer prodrug CPT-11
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| - | {{Clear}}
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| - | <applet load='ACHE1.pdb' size='500' frame='true' align='right'
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| - | scene='1w4l/Al/1' />
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| - | Described in the page '[[AChE inhibitors and substrates]]' <scene name='1w4l/Al/2'>galanthamine</scene> <font color='red'><b>(GAL; colored red)</b></font> is an AChE inhibitor and it is currently used in therapy of the AD. Conjugate of GAL through <scene name='1w4l/Al/3'>alkyl linker</scene> (8 carbons, <font color='yellow'><b>yellow</b></font>) with a <scene name='1w4l/Al/4'>phthalimido moiety</scene> <font color='blueviolet'><b>(blueviolet)</b></font> called '''compound 3''' has a larger affinity for AChE than that of GAL alone. This is similar to previously described cases of bivalent ligands.
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| - | {{Clear}}
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| - | <applet load='ACHE1.pdb' size='500' frame='true' align='left'
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| - | scene='1w4l/Al/1' />
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| - | A comparison between the <scene name='1w4l/Comparison/1'>compound 3</scene> in complex with ''Tc''AChE ([[1w4l]]) and the <scene name='1w4l/Comparison/2'>galanthamine/TcAChE</scene> structure ([[1dx6]]) shows an identical binding mode of the <font color='red'><b>GAL-moiety (transparent red)</b></font> of '''compound 3''' to that of <font color='blue'><b>GAL alone (blue)</b></font> at the CAS. The <font color='gray'><b>PEG molecule (gray)</b></font> is located at the active site of galanthamine/''Tc''AChE structure. The alkyl linker spans the active-site gorge and phthalimido moiety of the '''compound 3''' is situated near the Trp279 at the PAS. The '''compound 3''' has larger affinity to ''Tc''AChE than GAL. It could be explained by increased number of interactions between '''compound 3''' (which interacts not only with residues within CAS but also within PAS) and ''Tc''AChE in comparison to GAL.
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| - | {{Clear}}
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| - | <applet load='1u65' size='500' frame='true' align='right' scene='1u65/Binding_site/3' />
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| - | The <scene name='1u65/Cpt_11/1'>CPT-11</scene> <font color='yellow'><b>(yellow)</b></font> interacted with 13 residues of the the <scene name='1u65/Binding_site/1'>active-site gorge</scene> from Trp84 at the bottom to Phe284 at the top ([[1u65]]). Nine of these residues were <scene name='1u65/Binding_site/2'>aromatic</scene> <font color='darkmagenta'><b>(Tyr70, Trp84, Tyr121, Trp279, Phe284, Phe330, Phe331, Tyr334, and His440; colored darkmagenta)</b></font>. The contacts made by the drug in the bottom of the gorge involved <scene name='1u65/Binding_site/6'>complementary surface contacts</scene> with Trp84, Tyr121, Phe331, and His440 and, especially, a stacking interaction with Phe330. The carbamate moiety of CPT-11 was located near the residues <scene name='1u65/Binding_site/4'>Phe331 and Tyr334</scene>. So, the <font color='magenta'><b>carbon C9 (shown in magenta)</b></font> of the carbamate linkage in CPT-11, was 9.3 Å from <scene name='1u65/Binding_site/5'>Ser200</scene> <font color='red'><b>Oγ, the nucleophilic atom </b></font> within the three catalytic residues Ser200, His440, and Glu327. The steric clashes between CPT-11 and ''Tc''AChE residues prevented positioning CPT-11 near the Ser200 Oγ (where hydrolysis could occur), therefore, ''Tc''AChE can not hydrolyze CPT-11.
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| - | {{Clear}}
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| - | <applet load='ACHE3.pdb' size='500' frame='true' align='right'
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| - | scene='1e3q/Cv/1' />
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| - | Similarly to the other AChE bivalent inhibitors, <font color='magenta'><b>BW284C51 (BW)</b></font> also binds the ''Tc''AChE ([[1e3q]]) at the both subsites: CAS and PAS of its <scene name='1e3q/Active_site/1'>active site</scene>. At the CAS, BW makes a cation-aromatic interaction via quaternary group with <scene name='1e3q/Active_site/2'>Trp84</scene> <font color='orange'><b>(colored orange)</b></font>, BW phenyl ring forms an aromatic-aromatic interaction with His440, there is also an electrostatic interaction between the BW proximal quaternary group and Glu199. Near the PAS, BW via its distal quaternary group interacts with <scene name='1e3q/Active_site/3'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> and forms an aromatic interaction with Tyr334. BW forms hydrogen bond with Tyr121 OH, and makes alkyl interactions with Phe331. The superposition of BW with two other AChE bivalent inhibitors <scene name='1e3q/Active_site/4'>DECA</scene> <font color='gray'><b>(decamethonium, colored gray, [[1acl]])</b></font> and <scene name='1e3q/Active_site/5'>E2020</scene> <font color='blueviolet'><b>(Aricept, colored blueviolet, [[1eve]])</b></font> at the ''Tc''AChE active site reveals similar mode of binding. All these 3 inhibitors form cation-π and π-π interactions with active-site gorge aromatic residues <scene name='1e3q/Active_site/6'>(Tyr70, Trp84, Trp279 and Phe330 or Tyr334)</scene> <font color='yellow'><b>(colored yellow)</b></font>. The superposition of <scene name='1e3q/Active_site/7'>DECA and E2020</scene> reveals their similar position at the active site, but <scene name='1e3q/Active_site/8'>BW</scene> has a different trajectory from them. This causes the <scene name='1e3q/Active_site/9'>different conformation of Phe330</scene>, which interacts stronger with BW than with DECA and E2020. However, the conformations of the other important residues at the active site are similar in all these inhibitor-''Tc''AChE complexes.
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| - | It has been shown experimentally that BW and E2020 bind to ''Tc''AChE approximately 100-fold stronger than DECA. These findings could be explained by several reasons: ''i)'' E2020 and BW are less flexible than DECA; ''ii)'' the aromatic groups of E2020 and BW form favourable π-π interactions with ''Tc''AChE aromatic residues, in contrast to DECA; and ''iii)'' <scene name='1e3q/Shape/3'>BW</scene> and <scene name='1e3q/Shape/2'>E2020</scene> have aromatic groups and, therefore, occupy more volume and better fit the active-site gorge, than <scene name='1e3q/Shape/4'>string-shaped DECA</scene>. Mutations at the mouse or chicken AChE residues, corresponding to the ''Tc''AChE <scene name='1e3q/Active_site/10'>Tyr70, Trp84, Trp279 and Tyr121</scene> <font color='red'><b>(colored red)</b></font>, cause significant increase of inhibition constant values for all these 3 inhibitors, supporting the notion that these residues are critical for inhibitor-AChE binding.
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| - | {{Clear}}
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| - | <applet load='1eve' size='400' color='white' frame='true' spin='off' caption='Acetycholinesterase Binding E2020' align='left' />
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| - | Among the most interesting drugs that have been designed to inhibit
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| - | [[acetylcholinesterase]] are those that have two binding sites that bind both the peripheral and catatylic sites simultaneously. Such
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| - | drugs bind highly specificly and strongly. A good example is
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| - | <scene name='Acetylcholinesterase/1eve_e2020/1'>the E2020 (Aricept) complex</scene>.
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| - | It appears that the principal interaction between the aceylcholine and the enzyme is relatively newly discovered cation-pi interactions between the cationic moiety of the substrate and the many aromatic residues lining the catalytic gorge. Unlike most
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| - | interatomic interactions in chemistry, cation-pi interactions are unusual in that their energy hardly changes as the cationic and
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| - | aromatic ring centers vary between 4 and 7 Angstroms apart, and for a wide variety of relative orientations of the aromatic rings.
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| - | This gives the substrate an energetically smooth ride down the gorge with few bumps or barriers to impede passage down the gorge.
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| - | Most acetylcholinesterases have a net negative charge and a large patch of negative potential around the entrance to the active site gorge, which may be useful to attract the positively charged acetycholine substrate to the site. As one travels down the gorge, this potential becomes increasingly more and more negative, reaching a peak at the active site at the base. Because of this potential, the peripherial site is thought to act like a substrate trap, that forces practically molecule of substrate that reaches
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| - | the peripheral site to travel down the gorge to the active site, that probably contributes greatly to the extremely rapid rate of degrading the substrate. This whole enzyme therefore acts like a brilliantly designed natural vacuum cleaner that clears the
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| - | neurotransmitter out of the synapse extremely quickly. Yet to be solved, however, is how the products clear the active site rapidly,
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| - | whether back through the gorge, or out a back door on the other side of the protein that quickly opens each catalytic cycle (Trp 84
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| - | is actually near the surface of the 'underside' of the protein.)
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| - | {{Clear}}
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| - | ==References==
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| - | <ref group='xtra'>PMID:12351819</ref> <ref group='xtra'>PMID:10368299</ref> <ref group='xtra'>PMID:15772291</ref> <references group='xtra'/>
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| - | <ref group='xtra'>PMID:1678899</ref> <ref group='xtra'>PMID:15563167</ref> <references group='xtra'/>
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