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| - | ==AChE bivalent inhibitors==
| + | #REDIRECT [[AChE inhibitors and substrates]] |
| - | '''This page is a continuation of the page "[[AChE inhibitors and substrates]]".'''
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| - | <applet load='ZGBm.pdb' size='500' frame='true' align='right' scene='1zgb/Com_view/1' />
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| - | The <scene name='1zgb/Act_site/3'>active site</scene> of ''Tc''AChE consists of two binding subsites. First of them is the "catalytic anionic site" (CAS), which involves mentioned above catalytic triad <scene name='1zgb/Act_site/8'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the conserved residues <scene name='1zgb/Act_site/5'>Trp84</scene> and <scene name='1zgb/Act_site/10'>Phe330</scene> also participating in ligands recognition. Another conserved residue <scene name='1zgb/Act_site/11'>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. Therefore, the ligands that will be able to interact with both these subsites, will be more potent AChE inhibitors in comparison to compounds interacting only with CAS. One of the ways to produce such ligands is to introduce two active substances into one compound. If it is spatially necessary these subunits could be divided by alkyl linker with suitable length. According to the strategy of the use of a bivalent ligand, the <scene name='1zgb/Comp/7'>inhibitor</scene> '''(''RS'')-(±)-tacrine-(10)-hupyridone''' ((R)-3 or (S)-3) was designed and synthesized. It consists of mentioned in the page '[[AChE inhibitors and substrates]]' <scene name='1zgb/Comp/8'>tacrine</scene> <font color='magenta'><b>(colored magenta)</b></font>, 10-carbon <scene name='1zgb/Comp/9'>linker</scene> <font color='yellow'><b>(yellow)</b></font>, and <scene name='1zgb/Comp/10'>hupyridone</scene> <font color='red'><b>(red)</b></font>. The tacrine moiety of this inhibitor binds at the CAS, the linker spans the <scene name='1zgb/Act_site/12'>active-site</scene> gorge, and the hupyridone moiety binds at the PAS.
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| - | <applet load='ZGBm1.pdb' size='500' frame='true' align='left' scene='1zgb/Align/1' />
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| - | The comparison of the (R)-3/''Tc''AChE and tacrine/''Tc''AChE complexes at the <scene name='1zgb/Align/2'>active site</scene>. A <scene name='1zgb/Align/7'>comparison</scene> of the trigonal (R)-3/''Tc''AChE structure <font color='cyan'><b>(R)-3 colored cyan</b></font> (''Tc''AChE residues interacting with (R)-3 are colored sea-green) with the crystal structure of tacrine/''Tc''AChE ([[1acj]], (<font color='magenta'><b>tacrine colored magenta</b></font>; residues interacting with tacrine are colored <font color='pink'><b>pink</b></font>) reveals a similar binding mode for the tacrine moiety. In both structures the tacrine ring is situated at the CAS, between the aromatic residues Trp84 and Phe330. Steric clash with the 10-carbon linker could explain the tilt observed for the Phe330 <font color='yellow'><b> (yellow</b></font> and transparent in the tacrine/''Tc''AChE). <font color='red'><b>Water molecules are shown as red spheres.</b></font>
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| - | The tacrine unit of (R)-3 N forms <scene name='1zgb/Align/8'>hydrogen bond</scene> with His440 O (3.0 Å) similar to that of tacrine alone. Similarly to the tacrine/''Tc''AChE structure the <font color='red'><b>system of three water molecules</b></font> at the CAS ((R)-3/''Tc''AChE) binds the tacrine-linker N via hydrogen bonds to Ser81 O, Ser122 Oγ, and Asn85 Oδ1 (2.6-3.5 Å) .
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| - | <applet load='ZGBm5.pdb' size='500' frame='true' align='right' scene='1zgb/Align2/1' />
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| - | The comparison of the (R)-3/''Tc''AChE and bis-hupyridone/''Tc''AChE complexes ([[1h22]] and [[1h23]]) at the <scene name='1zgb/Align2/2'>active site</scene>. <scene name='1zgb/Align2/8'>Superposition</scene> of the <font color='cyan'><b>(''R'')-tacrine-(10)-hupyridone ((R)-3, cyan)</b></font> and <font color='orange'><b>(S,S)-(-)-''Bis''(12)-hupyridone ('''(S,S)-(-)-4b''', orange, ''i.e.'' 12-carbon-tether-linked hupyridone dimer)</b></font> and <font color='plum'><b>(S,S)-(-)-''Bis''(10)-hupyridone ('''(S,S)-(-)-4a''', plum)</b></font> complexes demonstrates the binding mode of the hupyridone moiety. <font color='magenta'><b>TcAChE residues of symmetry-related molecule are shown in magenta.</b></font> X-ray structures of ''Tc''AChE complexed with these 10- and 12-carbon-tether-linked 2 <scene name='1zgb/Align2/9'>dimers</scene> <font color='plum'><b>(S,S)-(-)-4a</b></font> and <font color='orange'><b>(S,S)-(-)-4b</b></font> show one subunit bound at the <scene name='1zgb/Align2/10'>CAS</scene>, the linker spanning the gorge, and the other subunit bound at the <scene name='1zgb/Align2/11'>PAS</scene>.
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| - | There are two <scene name='1zgb/Align2/12'>hydrogen bonds</scene> connecting the <font color='cyan'><b>hupyridone</b></font> <font color='red'><b>O</b></font> to <font color='magenta'><b>Lys11</b></font> <font color='blue'><b>Nζ</b></font> and <font color='cyan'><b>hupyridone</b></font> <font color='blue'><b>N</b></font> to <font color='magenta'><b>Gln185</b></font> <font color='red'><b>Oε1</b></font> of a <font color='magenta'><b>symmetry-related molecule</b></font> at <font color='cyan'><b>(R)-3</b></font>/''Tc''AChE complex. <font color='red'><b>Water molecules are shown as red spheres.</b></font> Another hydrogen bond connects the <font color='cyan'><b>hupyridone</b></font> <font color='red'><b>O</b></font> to a water molecule, which is bound to Ser286 N. Similarly, the hupyridone-PAS unit of both <font color='plum'><b>(-)-4a</b></font> and <font color='orange'><b>(-)-4b</b></font> forms direct and an indirect hydrogen bonds with the protein backbone in the PAS region.
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| - | <applet load='ZGCBm.pdb' size='500' frame='true' align='right' scene='1zgc/Al/1' />
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| - | The <scene name='1zgc/Al/4'>comparison</scene> of <font color='cyan'><b>(R)-3 (cyan)</b></font> and <font color='orange'><b>(S)-3 (orange)</b></font> bound to the ''Tc''AChE active site in the orthorhombic forms is shown. The residues important for inhibitor binding are in green. In contrast to the trigonal form ([[1zgb]]), the residues Gln*185 and Lys*11 <font color='yellow'><b>(yellow)</b></font> of an other symmetry-related monomer do not form hydrogen bonds with the ligands. <scene name='1zgc/Zgc_h22/2'>Superposition</scene> of <font color='magenta'><b>(S,S)-(-)-4a (magenta)</b></font> and <font color='orange'><b>(S)-3 (orange, orthorhombic ''Tc''AChE)</b></font> demonstrates the similar mode of binding of the hupyridone unit at the PAS. The residues Trp279 (top) and Trp84 (bottom) represent the PAS and the CAS, respectively.
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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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| - | <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 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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| - | <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. 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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| - | <applet load='1eve' size='400' color='white' frame='true' spin='off' caption='Acetycholinesterase Binding E2020' align='right' />
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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 (Try 84
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| - | is actually near the surface of the 'underside' of the protein.)
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| - | ==References==
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| - | Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein., Sussman JL, Harel M, Frolow F, Oefner C, Goldman A, Toker L, Silman I, Science. 1991 Aug 23;253(5022):872-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/1678899 1678899]
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| - | The complex of a bivalent derivative of galanthamine with torpedo acetylcholinesterase displays drastic deformation of the active-site gorge: implications for structure-based drug design., Greenblatt HM, Guillou C, Guenard D, Argaman A, Botti S, Badet B, Thal C, Silman I, Sussman JL, J Am Chem Soc. 2004 Dec 1;126(47):15405-11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15563167 15563167]
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| - | The crystal structure of the complex of the anticancer prodrug 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin (CPT-11) with Torpedo californica acetylcholinesterase provides a molecular explanation for its cholinergic action., Harel M, Hyatt JL, Brumshtein B, Morton CL, Yoon KJ, Wadkins RM, Silman I, Sussman JL, Potter PM, Mol Pharmacol. 2005 Jun;67(6):1874-81. Epub 2005 Mar 16. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15772291 15772291]
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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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