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==Design and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitors== | ==Design and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitors== | ||
<StructureSection load='4i1c' size='340' side='right' caption='[[4i1c]], [[Resolution|resolution]] 2.00Å' scene=''> | <StructureSection load='4i1c' size='340' side='right' caption='[[4i1c]], [[Resolution|resolution]] 2.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4i1c]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4i1c]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I1C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I1C FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BE:N-(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)-3-[2-PROPYL-4-(1H-PYRAZOL-4-YL)THIOPHEN-3-YL]-L-ALANINE'>1BE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1BE:N-(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)-3-[2-PROPYL-4-(1H-PYRAZOL-4-YL)THIOPHEN-3-YL]-L-ALANINE'>1BE</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4i12|4i12]], [[4i10|4i10]], [[4i0z|4i0z]], [[4i0g|4i0g]], [[4i0f|4i0f]], [[4i0e|4i0e]], [[4i0d|4i0d]], [[4hzi|4hzi]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4i12|4i12]], [[4i10|4i10]], [[4i0z|4i0z]], [[4i0g|4i0g]], [[4i0f|4i0f]], [[4i0e|4i0e]], [[4i0d|4i0d]], [[4hzi|4hzi]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BACE1, BACE, KIAA1149 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Memapsin_2 Memapsin 2], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.46 3.4.23.46] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4i1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i1c OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4i1c RCSB], [http://www.ebi.ac.uk/pdbsum/4i1c PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4i1c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i1c OCA], [http://pdbe.org/4i1c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4i1c RCSB], [http://www.ebi.ac.uk/pdbsum/4i1c PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4i1c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4i1c" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: | [[Category: Human]] | ||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Brecht, E]] | [[Category: Brecht, E]] | ||
Revision as of 06:39, 5 August 2016
Design and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitorsDesign and synthesis of thiophene dihydroisoquinolins as novel BACE-1 inhibitors
Structural highlights
Function[BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase.[1] [2] Publication Abstract from PubMedUtilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50=8nM) was made from a weak muM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed. Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors.,Xu YZ, Yuan S, Bowers S, Hom RK, Chan W, Sham HL, Zhu YL, Beroza P, Pan H, Brecht E, Yao N, Lougheed J, Yan J, Tam D, Ren Z, Ruslim L, Bova MP, Artis DR Bioorg Med Chem Lett. 2013 May 15;23(10):3075-80. doi:, 10.1016/j.bmcl.2013.03.009. Epub 2013 Mar 21. PMID:23570791[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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