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4joo

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Revision as of 11:28, 24 November 2022

Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

Structural highlights

4joo is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

A hallmark of Alzheimer's disease is the brain deposition of amyloid beta (Ass), a peptide of 36-43 amino acids that is likely a primary driver of neurodegeneration. Ass is produced by the sequential cleavage of APP by BACE1 and gamma-secretase; therefore, inhibition of BACE1 represents an attractive therapeutic target to slow or prevent Alzheimer's disease. Herein we describe BACE1 inhibitors with limited molecular flexibility and molecular weight that decrease CSF Ass in vivo, despite efflux. Starting with spirocycle 1a, we explore structure activity relationships of core changes, P3 moieties and Asp binding functional groups in order to optimize BACE1 affinity, cathepsin D selectivity, and blood-brain barrier (BBB) penetration. Using wild type guinea pig and rat, we demonstrate a PK/PD relationship between free drug concentrations in the brain and CSF Ass lowering. Optimization of brain exposure led to the discovery of (R)-50 which reduced CSF Ass in rodents and in monkey.

Spirocyclic ss-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid Beta in a Higher Species.,Hunt KW, Cook AW, Watts RJ, Clark CT, Vigers G, Smith D, Metcalf AT, Gunawardana IW, Burkard M, Cox AA, Geck-Do M, Dutcher D, Thomas AA, Rana S, Kallan NC, Delisle RK, Rizzi JP, Regal K, Sammond D, Groneberg R, Siu M, Purkey H, Lyssikatos JP, Marlow A, Liu X, Tang TP J Med Chem. 2013 Mar 28. PMID:23537249^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Hunt KW, Cook AW, Watts RJ, Clark CT, Vigers G, Smith D, Metcalf AT, Gunawardana IW, Burkard M, Cox AA, Geck-Do M, Dutcher D, Thomas AA, Rana S, Kallan NC, Delisle RK, Rizzi JP, Regal K, Sammond D, Groneberg R, Siu M, Purkey H, Lyssikatos JP, Marlow A, Liu X, Tang TP. Spirocyclic ss-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors: From Hit to Lowering of Cerebrospinal Fluid (CSF) Amyloid Beta in a Higher Species. J Med Chem. 2013 Mar 28. PMID:23537249 doi:http://dx.doi.org/10.1021/jm4002154

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4joo"

Categories: Homo sapiens | Large Structures | Smith D | Vigers GPA

@@ Line 1: / Line 1: @@
 ==Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors==
-<StructureSection load='4joo' size='340' side='right' caption='[[4joo]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
+<StructureSection load='4joo' size='340' side='right'caption='[[4joo]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4joo]] 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=4JOO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JOO FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4joo]] 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=4JOO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JOO FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1M4:(4R)-2-AMINO-6-BROMO-1,2,2-TRIMETHYL-2,3-DIHYDROSPIRO[CHROMENE-4,4-IMIDAZOL]-5(1H)-ONE'>1M4</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1M4:(4R)-2-AMINO-6-BROMO-1,2,2-TRIMETHYL-2,3-DIHYDROSPIRO[CHROMENE-4,4-IMIDAZOL]-5(1H)-ONE'>1M4</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4jpe|4jpe]], [[4jp9|4jp9]], [[4jpc|4jpc]]</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=4joo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4joo OCA], [https://pdbe.org/4joo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4joo RCSB], [https://www.ebi.ac.uk/pdbsum/4joo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4joo ProSAT]</span></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='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=4joo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4joo OCA], [http://pdbe.org/4joo PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4joo RCSB], [http://www.ebi.ac.uk/pdbsum/4joo PDBsum]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 20: @@
 ==See Also==
-*[[Beta secretase|Beta secretase]]
+*[[Beta secretase 3D structures|Beta secretase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
-[[Category: Memapsin 2]]
+[[Category: Large Structures]]
-[[Category: Smith, D]]
+[[Category: Smith D]]
-[[Category: Vigers, G P.A]]
+[[Category: Vigers GPA]]
-[[Category: Aspartyl protease]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]

4joo

From Proteopedia

Revision as of 11:28, 24 November 2022

Spirocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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