|
|
| (11 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | ==PART I. Tacrine- and hupyridone-containing compounds==
| + | #REDIRECT [[AChE inhibitors and substrates]] |
| - | '''This page is a continuation of the pages [[AChE inhibitors and substrates]] and [[AChE inhibitors and substrates (Part II)]].'''
| + | |
| - | | + | |
| - | * [[1zgb]] Complex with (''R'')-tacrine-(10)-hupyridone (cmp '''R-3''')
| + | |
| - | * [[1zgc]] Complex with (''S'')-tacrine-(10)-hupyridone (cmp '''S-3''')
| + | |
| - | * [[1acj]] Complex with tacrine alone
| + | |
| - | * [[1h22]] Complex with (S,S)-(-)-''Bis''(12)-hupyridone (cmp '''(S,S)-(-)-4b''')
| + | |
| - | * [[1h23]] Complex with (S,S)-(-)-''Bis''(10)-hupyridone (cmp '''(S,S)-(-)-4a''')
| + | |
| - | * [[2cmf]] Complex with Bis(5)-tacrine derivative (cmp '''2d''')
| + | |
| - | * [[2ckm]] Complex with Bis(7)-tacrine derivative (cmp '''2f''')
| + | |
| - | * [[1ut6]] Complex with N-9-(1',2',3',4'-TETRAHYDROACRIDINYL)-1,8-DIAMINOOCTANE (cmp '''6''')
| + | |
| - | * [[1odc]] Complex with cmp '''7'''
| + | |
| - | | + | |
| - | <applet load='ZGBm.pdb' size='500' frame='true' align='right' scene='1zgb/Com_view/1' />
| + | |
| - | | + | |
| - | The <scene name='1zgb/Act_site/3'>active site</scene> of ''Tc''AChE consists of two binding subsites. One of them is the "catalytic anionic site" (CAS), which contains the 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> which participate in ligand recognition. Another conserved residue <scene name='1zgb/Act_site/11'>Trp279</scene> <font color='cyan'><b>(colored cyan)</b></font> is situated at a second binding subsite, termed the "peripheral anionic site" (PAS), ~14 Å from CAS. Therefore, ligands that can interact with both these subsites, are expected to be more potent AChE inhibitors than inhibitors interacting with CAS only. One of the ways to produce such ligands is to introduce two inhibitor moieties in one compound. If it is spatially required, these subunits could be separated 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 <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='black'><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.
| + | |
| - | {{Clear}}
| + | |
| - | | + | |
| - | <applet load='ZGBm1.pdb' size='500' frame='true' align='left' scene='1zgb/Align/1' />
| + | |
| - | | + | |
| - | Shown is the overlap of the (R)-3/''Tc''AChE and tacrine/''Tc''AChE complexes at the <scene name='1zgb/Align/2'>active site</scene>. <scene name='1zgb/Align/7'>Overlap</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='black'><b> (yellow</b></font> and transparent in the tacrine/''Tc''AChE). <font color='red'><b>Water molecules are shown as red spheres.</b></font>
| + | |
| - | The N atom of the tacrine moiety of (R)-3 forms a <scene name='1zgb/Align/8'>hydrogen bond</scene> with His440 O (3.0 Å) similar to the one seen in the tacrine/''Tc''AChE. The tacrine/''Tc''AChE structure shows the <font color='red'><b>system of three water molecules</b></font> at the CAS where ((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) .
| + | |
| - | {{Clear}}
| + | |
| - | | + | |
| - | <applet load='ZGBm5.pdb' size='500' frame='true' align='right' scene='1zgb/Align2/1' />
| + | |
| - | | + | |
| - | The overlap 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> is shown. <scene name='1zgb/Align2/8'>Superposition</scene> of the ''Tc''AChE complexes of <font color='cyan'><b>(''R'')-tacrine-(10)-hupyridone ((R)-3, cyan)</b></font>, <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> demonstrates the binding mode of the hupyridone moiety. <font color='magenta'><b>''Tc''AChE 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 <scene name='1zgb/Align2/9'>bifunctional inhibitors</scene> <font color='plum'><b>(S,S)-(-)-4a</b></font> and <font color='orange'><b>(S,S)-(-)-4b</b></font> show one moiety bound at the <scene name='1zgb/Align2/10'>CAS</scene>, the linker spanning the gorge, and the other moiety bound at the <scene name='1zgb/Align2/11'>PAS</scene>.
| + | |
| - | 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> in the <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 moiety at the PAS site of both <font color='plum'><b>(-)-4a</b></font> and <font color='orange'><b>(-)-4b</b></font> complexes forms direct and water-mediated hydrogen bonds with the protein backbone.
| + | |
| - | {{Clear}}
| + | |
| - | | + | |
| - | <applet load='ZGCBm.pdb' size='500' frame='true' align='left' scene='1zgc/Al/1' />
| + | |
| - | | + | |
| - | The <scene name='1zgc/Al/5'>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. <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.
| + | |
| - | | + | |
| - | {{Clear}}
| + | |
| - | | + | |
| - | <applet load='2cmf' size='500' frame='true' align='right'
| + | |
| - | scene='2cmf/Comparison/1' />
| + | |
| - | '''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 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 alone</b></font> ([[1acj]]). The second tacrine moiety of the '''2d''' interacts with peripheral anionic site (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 the <font color='cyan'><b>native structure</b></font> ([[2ace]]). This binding results in <scene name='2cmf/Comparison/4'>major structural changes</scene> in the Val281-Ser291 loop causing a significant change in the surface of the active-site gorge in comparison to the <font color='cyan'><b>native structure</b></font> ([[2ace]]). The first tacrine moiety 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 the first tacrine moiety of the '''2d''' at the CAS. The second tacrine moiety of the '''2f''' interacts with PAS near the Trp279, similar to '''2d'''. The <scene name='2cmf/Comparison/6'>binding</scene> of the '''2f''' does not cause significant structural changes in the <font color='plum'><b>''Tc''AChE</b></font> upon forming the complex in comparison to the <font color='cyan'><b>native ''Tc''AChE structure</b></font>. <scene name='2cmf/Comparison/7'>Comparison</scene> of the <font color='magenta'><b>2d</b></font> and <font color='orange'><b>2f</b></font> reveals different contacts between the second tacrine moieties of these compounds and ''Tc''AChE. There are two additional structures of tacrine-containing AChE inhibitors: compounds <scene name='2cmf/Comparison/8'>6</scene> ([[1ut6]]) and <scene name='2cmf/Comparison/9'>7</scene> ([[1odc]]). The tacrine moieties of these compounds also adopt similar conformations and interactions with CAS as tacrine alone, '''2f''' and '''2d'''. Both inhibitors '''6''' and '''7''' are spanning the <scene name='2cmf/Comparison/10'>active-site gorge</scene> from the CAS up to 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 (cyan), ''Tc''AChE-'''cmp 6''' complex (white), and ''Tc''AChE-'''cmp 7''' complex (crimson) , except of Trp279, all the other ''Tc''AChE active-site gorge residues have similar conformations.
| + | |
| - | {{Clear}}
| + | |
| - | | + | |
| - | '''For information about additional AChE inhibitors see page [[AChE bivalent inhibitors (Part II)]].'''
| + | |
| - | | + | |
| - |
| + | |
| - | ==References==
| + | |
| - | <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'/>
| + | |
| - | | + | |
| - | [[Category: catalytic triad]]
| + | |
| - | [[Category: cholinesterase]]
| + | |
| - | [[Category: acetylcholinesterase]]
| + | |
| - | [[Category: AChE inhibitors and substrates]]
| + | |
| - | [[Category: inhibitor]]
| + | |
| - | [[Category: cholinesterases]]
| + | |
| - | [[Category: acetylcholine]]
| + | |
| - | [[Category: cation-pi]]
| + | |
| - | [[Category: Alzheimer's]]
| + | |
| - | [[Category: nerve gasses]]
| + | |
