AChE bivalent inhibitors (Part II)

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'''This page is a continuation of the page [[AChE bivalent inhibitors]]'''
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#REDIRECT [[AChE inhibitors and substrates]]
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* [[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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* [[1e3q]] ''Tc''AChE complex with BW284C51
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* [[1acl]] ''Tc''AChE complex with decamethonium
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* [[1eve]] ''Tc''AChE complex with Aricept
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* [[1jjb]] ''Tc''AChE complex with PEG-SH-350
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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 (Part II)]]' <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 the <scene name='1w4l/Al/3'>alkyl linker</scene> (8 carbons, <font color='black'><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 <scene name='1w4l/Comparison/1'>compound 3</scene>/''Tc''AChE ([[1w4l]]) and <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. A <font color='gray'><b>PEG molecule (gray)</b></font> is located at the active site of the galanthamine/''Tc''AChE structure. The alkyl linker spans the active-site gorge and the phthalimido moiety of '''compound 3''' is situated near Trp279 at the PAS. '''Compound 3''' has higher affinity to ''Tc''AChE than GAL. This can be explained by the higher number of interactions between '''compound 3''' (which interacts not only with residues within CAS but also within PAS) and ''Tc''AChE relative 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 drug <scene name='1u65/Cpt_11/1'>CPT-11</scene> <font color='black'><b>(yellow)</b></font> interacts with 13 residues of 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 are <scene name='1u65/Binding_site/2'>aromatic</scene> <font color='darkmagenta'><b>(Tyr70, Trp84, Tyr121, Trp279, Phe284, Phe330, Phe331, Tyr334, and His440; colored dark magenta)</b></font>. The contacts made by the drug at the bottom of the gorge involves <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 is seen near residues <scene name='1u65/Binding_site/4'>Phe331 and Tyr334</scene>. <font color='magenta'><b>Carbon C9 (shown in magenta)</b></font> of the carbamate linkage in CPT-11, is 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 bar the positioning of CPT-11 near 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='left'
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scene='1e3q/Cv/1' />
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In a similar fashion to other AChE bivalent inhibitors, <font color='magenta'><b>BW284C51 (BW)</b></font> binds to ''Tc''AChE ([[1e3q]]) at both subsites of its <scene name='1e3q/Active_site/1'>active site</scene> - CAS and PAS. At the CAS, the BW makes a cation-aromatic interaction via its quaternary group to <scene name='1e3q/Active_site/2'>Trp84</scene> <font color='orange'><b>(colored orange)</b></font>. The 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 gorge reveals similar mode of binding. 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='black'><b>(colored yellow)</b></font>. The superposition of <scene name='1e3q/Active_site/7'>DECA and E2020</scene> reveals their similar trajectory along the active site gorge, but <scene name='1e3q/Active_site/8'>BW</scene> has a different one. This results in <scene name='1e3q/Active_site/9'>different conformation of Phe330</scene>, which interacts with BW more strongly than with DECA and E2020. The conformations of the other important residues at the active site are similar in all these inhibitor 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 have several explanations: ''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='1jjb.pdb' size='500' frame='true' align='right'
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scene='1jjb/Cv/4' />
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<scene name='1jjb/Active_site/1'>PEG-SH-350</scene> is an untypical bivalent acetylcholinesterase inhibitor ([[1jjb]]). In contrast to other acetylcholinesterase inhibitors, it has not cationic moieties. It consists of heptameric polyethylene glycol with a thiol group at the terminus. This thiol group binds close to the <scene name='1jjb/Active_site/4'>CAS</scene>, while its second terminus binds to the <scene name='1jjb/Active_site/5'>PAS</scene>. PEG-SH-350 interacts with ''Tc''AChE via a system of <scene name='1jjb/Active_site/6'>water molecules</scene> <font color='red'><b>(represented by oxygens colored red)</b></font>. Two out of the seven PEG-SH-350 ethylene glycol units are in a ''trans'' <scene name='1jjb/Active_site/7'>conformation</scene> <font color='blue'><b>(colored blue)</b></font>, while the others are in ''±gauche'' <scene name='1jjb/Active_site/8'>conformation</scene>.
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{{Clear}}
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<applet load='1eve.pdb' size='500' frame='true' align='right' scene='Main_Page/E2020_in_ache_spinning/1' />
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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 strongly and with high specificly. A good example is
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<scene name='Acetylcholinesterase/1eve_e2020/1'>the E2020/''Tc''AChE (Aricept) complex</scene> ([[1eve]]).
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It appears that the principal interaction between the aceylcholine and the enzyme is the relatively newly discovered cation-pi interaction 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 distance vary between 4 and 7 Angstroms, 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. This 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 every molecule of substrate that reaches
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the peripheral site to travel down the gorge to the active site. This 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 (Trp84
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is actually near the surface at the 'underside' of the protein).
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The X-ray structure of the E2020-''Tc''AChE complex shows that E2020 has a <scene name='1eve/E2020_close_up_with_84_279/13'>unique orientation</scene> along the active-site gorge, extending from the anionic subsite (<scene name='1eve/E2020_close_up_with_84lbld/7'>W84</scene>) of the active site, at the bottom, to the peripheral anionic site (<scene name='1eve/E2020_close_up_with_84_279lbld/5'>near W279</scene>), at the top, via aromatic stacking interactions with conserved aromatic acid residues. E2020 does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only <scene name='1eve/E20_interactionshown/8'>indirectly via solvent molecules</scene>.
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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>
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<ref group='xtra'>PMID:12095250</ref> <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 and substrates]]
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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]]
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[[Category: nerve gasses]]
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[[Category: ISPC, Israel Structural Proteomics Center.]]
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[[Category: ISPC]]
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[[Category: Israel Structural Proteomics Center]]
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Current revision

  1. REDIRECT AChE inhibitors and substrates

Proteopedia Page Contributors and Editors (what is this?)

Alexander Berchansky, David Canner, Michal Harel

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