3s7l

From Proteopedia

(Difference between revisions)

Revision as of 04:27, 5 August 2016

Pyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors

Structural highlights

3s7l is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3s7m
Gene:	BACE1, BACE, KIAA1149 (HUMAN)
Activity:	Memapsin 2, with EC number 3.4.23.46
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

The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. SAR studies of the S2' region of the BACE1 ligand binding pocket with pyrazolyl and thienyl P2' side chains are reported. These analogs exhibit low nanomolar potency for BACE1, and demonstrate >50- to 100-fold selectivity for the structurally related aspartyl proteases BACE2 and cathepsin D. Small groups attached at the nitrogen of the P2' pyrazolyl moiety, together with the P3 pyrimidine nucleus projecting into the S3 region of the binding pocket, are critical components to ligand's potency and selectivity. P2' thiophene side chain analogs are highly potent BACE1 inhibitors with excellent selectivity against cathepsin D, but only modest selectivity against BACE2. The cell-based activity of these new analogs tracked well with their increased molecular binding with EC(50) values of 0.07-0.2muM in the ELISA assay for the most potent analogs.

New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2' region.,Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, Johnson M, Robichaud A, Zhou P, Yan Y, Solvibile W, Turner J, Fan KY, Chopra R, Bard J, Pangalos MN Bioorg Med Chem Lett. 2011 Sep 15;21(18):5164-70. Epub 2011 Jul 23. PMID:21835615^[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
↑ Malamas MS, Erdei J, Gunawan I, Barnes K, Hui Y, Johnson M, Robichaud A, Zhou P, Yan Y, Solvibile W, Turner J, Fan KY, Chopra R, Bard J, Pangalos MN. New pyrazolyl and thienyl aminohydantoins as potent BACE1 inhibitors: Exploring the S2' region. Bioorg Med Chem Lett. 2011 Sep 15;21(18):5164-70. Epub 2011 Jul 23. PMID:21835615 doi:10.1016/j.bmcl.2011.07.057

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/3s7l"

@@ Line 1: / Line 1: @@
 ==Pyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors==
 <StructureSection load='3s7l' size='340' side='right' caption='[[3s7l]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[3s7l]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3S7L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S7L FirstGlance]. <br>
+<table><tr><td colspan='2'>[[3s7l]] 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=3S7L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3S7L FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=591:(5S)-2-AMINO-5-(1-ETHYL-1H-PYRAZOL-4-YL)-3-METHYL-5-[3-(PYRIMIDIN-5-YL)PHENYL]-3,5-DIHYDRO-4H-IMIDAZOL-4-ONE'>591</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3s7m|3s7m]]</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 Homo sapiens])</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=3s7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7l OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3s7l RCSB], [http://www.ebi.ac.uk/pdbsum/3s7l 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=3s7l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3s7l OCA], [http://pdbe.org/3s7l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3s7l RCSB], [http://www.ebi.ac.uk/pdbsum/3s7l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3s7l ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3s7l" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Homo sapiens]]
+[[Category: Human]]
 [[Category: Memapsin 2]]
 [[Category: Chopra, R]]

3s7l

From Proteopedia

Revision as of 04:27, 5 August 2016

Pyrazolyl and Thienyl Aminohydantoins as Potent BACE1 Inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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