4fm7: Difference between revisions
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==Crystal Structure of BACE with Compound 14g== | ==Crystal Structure of BACE with Compound 14g== | ||
<StructureSection load='4fm7' size='340' side='right' caption='[[4fm7]], [[Resolution|resolution]] 1.56Å' scene=''> | <StructureSection load='4fm7' size='340' side='right'caption='[[4fm7]], [[Resolution|resolution]] 1.56Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4fm7]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[4fm7]] 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=4FM7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4FM7 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0UP:4-{[(5R,7S)-1-(3-FLUOROPHENYL)-3,7-DIMETHYL-2,2-DIOXIDO-2-THIA-1,3,8-TRIAZASPIRO[4.5]DEC-8-YL]METHYL}-2-(PROPAN-2-YLOXY)PHENOL'>0UP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.56Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0UP:4-{[(5R,7S)-1-(3-FLUOROPHENYL)-3,7-DIMETHYL-2,2-DIOXIDO-2-THIA-1,3,8-TRIAZASPIRO[4.5]DEC-8-YL]METHYL}-2-(PROPAN-2-YLOXY)PHENOL'>0UP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4fm7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4fm7 OCA], [https://pdbe.org/4fm7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4fm7 RCSB], [https://www.ebi.ac.uk/pdbsum/4fm7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4fm7 ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | |||
[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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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 4fm7" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Beta secretase|Beta secretase]] | *[[Beta secretase 3D structures|Beta secretase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Vajdos | [[Category: Vajdos FF]] | ||
[[Category: Varghese | [[Category: Varghese AH]] | ||
Latest revision as of 13:51, 6 November 2024
Crystal Structure of BACE with Compound 14gCrystal Structure of BACE with Compound 14g
Structural highlights
FunctionBACE1_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 PubMedbeta-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 AlsoReferences
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