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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='4i0e' size='340' side='right' caption='[[4i0e]], [[Resolution|resolution]] 1.70Å' scene=''> | + | <StructureSection load='4i0e' size='340' side='right'caption='[[4i0e]], [[Resolution|resolution]] 1.70Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4i0e]] 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=4I0E OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4I0E FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4i0e]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4I0E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4I0E FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1B8:3-[2-BROMO-4-(1H-PYRAZOL-4-YL)THIOPHEN-3-YL]-N-(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)-L-ALANINE'>1B8</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.7Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4i0d|4i0d]], [[4hzt|4hzt]], [[4i0f|4i0f]], [[4i0g|4i0g]], [[4i0z|4i0z]], [[4i10|4i10]], [[4i02|4i02]], [[4i0c|4i0c]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1B8:3-[2-BROMO-4-(1H-PYRAZOL-4-YL)THIOPHEN-3-YL]-N-(6-CHLORO-3,3-DIMETHYL-3,4-DIHYDROISOQUINOLIN-1-YL)-L-ALANINE'>1B8</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4i0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i0e OCA], [https://pdbe.org/4i0e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4i0e RCSB], [https://www.ebi.ac.uk/pdbsum/4i0e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4i0e ProSAT]</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=4i0e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4i0e OCA], [http://pdbe.org/4i0e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4i0e RCSB], [http://www.ebi.ac.uk/pdbsum/4i0e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4i0e ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> | + | [https://www.uniprot.org/uniprot/BACE1_HUMAN 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.<ref>PMID:10677483</ref> <ref>PMID:20354142</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Beta secretase|Beta secretase]] | + | *[[Beta secretase 3D structures|Beta secretase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Memapsin 2]] | + | [[Category: Large Structures]] |
| - | [[Category: Brecht, E]] | + | [[Category: Brecht E]] |
| - | [[Category: Yao, N]] | + | [[Category: Yao N]] |
| - | [[Category: Aspartic protease]]
| + | |
| - | [[Category: Bace]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Hydrolysis]]
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| 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 PubMed
Utilizing 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 Also
References
- ↑ Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
- ↑ Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
- ↑ 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. Design and synthesis of thiophene dihydroisoquinolines as novel BACE1 inhibitors. 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 doi:10.1016/j.bmcl.2013.03.009
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