AChE bivalent inhibitors

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==PART I. Tacrine- and hupyridone-containing compounds==
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#REDIRECT [[AChE inhibitors and substrates]]
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'''This page is a continuation of the pages [[AChE inhibitors and substrates]], [[AChE inhibitors and substrates (Part II)]], and [[AChE inhibitors and substrates (Part III)]].'''
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* [[1zgb]] Complex with (''R'')-tacrine-(10)-hupyridone (cmp '''R-3''')
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* [[1zgc]] Complex with (''S'')-tacrine-(10)-hupyridone (cmp '''S-3''')
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* [[1acj]] Complex with tacrine alone
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* [[1h22]] Complex with (S,S)-(-)-''Bis''(12)-hupyridone (cmp '''(S,S)-(-)-4b''')
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* [[1h23]] Complex with (S,S)-(-)-''Bis''(10)-hupyridone (cmp '''(S,S)-(-)-4a''')
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* [[2cmf]] Complex with Bis(5)-tacrine derivative (cmp '''2d''')
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* [[2ckm]] Complex with Bis(7)-tacrine derivative (cmp '''2f''')
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* [[1ut6]] Complex with N-9-(1',2',3',4'-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE (cmp '''6''')
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* [[1odc]] Complex with cmp '''7'''
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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 [http://en.wikipedia.org/wiki/Catalytic_triad catalytic triad] <scene name='1zgb/Act_site/8'>Ser200, His440, and Glu327</scene> <font color='orange'><b>(colored orange)</b></font> and the [http://en.wikipedia.org/wiki/Conserved_sequence#Conserved_protein_sequences_and_Structures 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 [http://en.wikipedia.org/wiki/Acetylcholinesterase_inhibitor 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 [http://en.wikipedia.org/wiki/Tacrine 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 [http://en.wikipedia.org/wiki/Aromaticity 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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{{Clear}}
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<applet load='ZGCBm.pdb' size='500' frame='true' align='left' scene='1zgc/Al/1' />
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The <scene name='1zgc/Al/5'>overlap</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. <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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{{Clear}}
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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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<font color='magenta'><b>2d</b></font> and <font color='orange'><b>2f</b></font> 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 tacrine moiety of <scene name='2cmf/Comparison/2'>2d</scene> at the ''Tc''AChE catalytic anionic site (CAS) is similar to that of <font color='red'><b>tacrine </b></font> in the tacrine/''Tc''AChE complex ([[1acj]]). The second tacrine moiety of the <font color='magenta'><b>2d</b></font> interacts with the peripheral anionic site (PAS) near Trp279. The interaction of <font color='magenta'><b>2d</b></font> at the CAS causes an 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) as seen in the <font color='cyan'><b>native structure</b></font> ([[2ace]]). The binding of 2d results in <scene name='2cmf/Comparison/4'>major structural changes</scene> in the Val281-Ser291 loop changing the surface of the active-site gorge from its <font color='cyan'><b>native conformation</b></font> ([[2ace]]). The tacrine moiety of the compound <font color='orange'><b>'''2f''' (heptylene-linked bis-tacrine</b></font> at the CAS, [[2ckm]]) adopts similar <scene name='2cmf/Comparison/5'>conformation</scene> as tacrine in the tacrine/''Tc''AChE complex and the tacrine moiety of the <font color='magenta'><b>2d</b></font> at the CAS. The second tacrine moiety of the <font color='orange'><b>2f</b></font> interacts with PAS near the Trp279, like <font color='magenta'><b>2d</b></font>. The <scene name='2cmf/Comparison/6'>binding</scene> of <font color='orange'><b>2f</b></font> does not cause significant structural changes in <font color='plum'><b>''Tc''AChE</b></font> from its <font color='cyan'><b>native structure</b></font>. <scene name='2cmf/Overlap/7'>Comparison</scene> of the structures of <font color='magenta'><b>2d</b></font>/''Tc''AChE and <font color='orange'><b>2f</b></font>/''Tc''AChE reveals different contacts between the tacrine moieties of these compounds at the PAS and ''Tc''AChE. There are two additional structures of tacrine-containing ''Tc''AChE complexes: compounds <scene name='2cmf/Comparison/8'>6</scene> ([[1ut6]]) and <scene name='2cmf/Comparison/9'>7</scene> ([[1odc]]). The tacrine moieties of these compounds adopt similar conformations and interactions with CAS as the tacrine in the tacrine/''Tc''AChE, <font color='orange'><b>2f</b></font>/''Tc''AChE and <font color='magenta'><b>2d</b></font>/''Tc''AChE. Inhibitors '''6''' and '''7''' are spanning the <scene name='2cmf/Comparison/10'>active-site gorge</scene> between the CAS and the PAS, but since compound '''7''' lacks the second tacrine moiety, Trp279 adopts a different conformation in this complex structure. In the three structures: native ''Tc''AChE (cyan), '''cmp 6'''/''Tc''AChE complex (white), and '''cmp 7'''/''Tc''AChE complex (crimson) , all the ''Tc''AChE active-site gorge residues have identical conformation except Trp279.
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{{Clear}}
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===Additional Resources===
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For additional information, see: [[Alzheimer's Disease]] <br />
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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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[[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, Jaime Prilusky

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