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| - | ==PART I==
| + | #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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| - | {{Clear}}
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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 ([[1zgb]]; <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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| - | {{Clear}}
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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 ([[1zgb]]) 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</b></font> ([[1zgc]]) 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</b></font> ([[1h22]]) and <font color='orange'><b>(S)-3, orthorhombic ''Tc''AChE</b></font> ([[1zgc]]) 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='2cmf' size='500' frame='true' align='right'
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| - | scene='2cmf/Comparison/1' />
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| - | '''2d''' and '''2f''' are bis(''n'')-tacrine derivatives with n=5 and 7 (number of carbons in the linkers), respectively. These compounds are more potent and selective AChE inhibitors than tacrine alone. The binding of the first ring of <scene name='2cmf/Comparison/2'>2d</scene> at the ''Tc''AChE CAS is similar to that of <font color='red'><b>tacrine itself</b></font> ([[1acj]]). The second ring of the '''2d''' interacts with PAS near the Trp279. The interaction of '''2d''' at CAS caused increase of the <scene name='2cmf/Comparison/3'>distance</scene> between Ser200 Oγ and H440 Nε2 atoms, and, therefore, disruption of the catalytic triad (Ser200, H220, E327) compared with <font color='cyan'><b>native structure</b></font> ([[2ace]]). This binding also caused <scene name='2cmf/Comparison/4'>major structural changes</scene> in the Val281-Ser291 loop resulting in significant change in the surface of the active-site gorge in compararison to <font color='cyan'><b>native structure</b></font> ([[2ace]]). The first ring of the compound <font color='orange'><b>'''2f''' (heptylene-linked bis-tacrine</b></font>, [[2ckm]]) also adopts similar <scene name='2cmf/Comparison/5'>conformation</scene> as tacrine alone and first ring of the '''2d''' at the CAS. The second tacrine ring of the '''2f''' also interacts with PAS near the Trp279, as well as '''2d'''. The <scene name='2cmf/Comparison/6'>binding</scene> of the '''2f''' did not cause significant structural changes in the <font color='plum'><b>TcAChE complexed with it</b></font> in comarison to <font color='cyan'><b>native structure</b></font> ([[2ace]]). Of course, <scene name='2cmf/Comparison/7'>comparison</scene> of the <font color='magenta'><b>2d</b></font> and <font color='orange'><b>2f</b></font> revealed significantly different contacts between second rings of these compounds with ''Tc''AChE.
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| - | '''For information about additional AChE inhibitors see page [[AChE bivalent inhibitors (Part II)]].'''
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| - | ==References==
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| - | <ref group='xtra'>PMID:1678899</ref> <ref group='xtra'>PMID:15563167</ref> <ref group='xtra'>PMID:15772291</ref> <ref group="xtra">PMID:16942022</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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