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| | ==Crystal Structure of BACE with Compound 12a== | | ==Crystal Structure of BACE with Compound 12a== |
| - | <StructureSection load='4fm8' size='340' side='right' caption='[[4fm8]], [[Resolution|resolution]] 1.90Å' scene=''> | + | <StructureSection load='4fm8' size='340' side='right'caption='[[4fm8]], [[Resolution|resolution]] 1.90Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4fm8]] 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=4FM8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4FM8 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4fm8]] 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=4FM8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FM8 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0UQ:(5R,7S)-1-(3-FLUOROPHENYL)-3,7-DIMETHYL-8-[3-(PROPAN-2-YLOXY)BENZYL]-2-THIA-1,3,8-TRIAZASPIRO[4.5]DECANE+2,2-DIOXIDE'>0UQ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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" id="ligandDat"><scene name='pdbligand=0UQ:(5R,7S)-1-(3-FLUOROPHENYL)-3,7-DIMETHYL-8-[3-(PROPAN-2-YLOXY)BENZYL]-2-THIA-1,3,8-TRIAZASPIRO[4.5]DECANE+2,2-DIOXIDE'>0UQ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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=4fm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm8 OCA], [https://pdbe.org/4fm8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fm8 RCSB], [https://www.ebi.ac.uk/pdbsum/4fm8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fm8 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>
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| - | <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=4fm8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm8 OCA], [http://pdbe.org/4fm8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4fm8 RCSB], [http://www.ebi.ac.uk/pdbsum/4fm8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4fm8 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: Vajdos, F F]] | + | [[Category: Vajdos FF]] |
| - | [[Category: Varghese, A H]] | + | [[Category: Varghese AH]] |
| - | [[Category: Aspartyl protease]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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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
beta-Secretase (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize CNS penetration by minimizing hydrogen bond donors (HBD) and reducing P-glycoprotein (P-gp) mediated efflux. We have also taken advantage of the combination of structure based drug design (SBDD) to guide the optimization of the sulfamide analogs and the in-silico tool WaterMap to explain the observed SAR. Compound 14g is a potent inhibitor of BACE-1 with excellent permeability and a moderate P-gp liability. Administration of 14g to mice produced a significant, dose-dependent reduction in central AbetaX-40 levels at a free drug exposure equivalent to the whole cell IC(50) (100 nM). Furthermore, studies in the P-gp knock-out mouse provided evidence that efflux transporters impacted the amount of Abeta lowering versus that observed in wild-type (WT) mouse at equivalent dose.
Spirocyclic Sulfamides as BACE-1 Inhibitors for the Treatment of Alzheimer's Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies to Identify Centrally Efficacious Inhibitors.,Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray JC, Vajdos FF, Ambroise C, Christoffersen C, Fisher KE, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov IV, Oborski CE, Varghese AH, O'Neill BT J Med Chem. 2012 Sep 17. PMID:22984865[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
- ↑ Brodney MA, Barreiro G, Ogilvie K, Hajos-Korcsok E, Murray JC, Vajdos FF, Ambroise C, Christoffersen C, Fisher KE, Lanyon L, Liu J, Nolan CE, Withka JM, Borzilleri KA, Efremov IV, Oborski CE, Varghese AH, O'Neill BT. Spirocyclic Sulfamides as BACE-1 Inhibitors for the Treatment of Alzheimer's Disease: Utilization of Structure Based Drug Design, WaterMap, and CNS Penetration Studies to Identify Centrally Efficacious Inhibitors. J Med Chem. 2012 Sep 17. PMID:22984865 doi:10.1021/jm3009426
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