4b1d

From Proteopedia

(Difference between revisions)

Current revision

New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain

Structural highlights

4b1d 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.
Method:	X-ray diffraction, Resolution 1.95Å
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

Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Abeta40 and Abeta42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Abeta was 40-50%, 1.5 h after oral dosing (100 mumol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.

New Aminoimidazoles as beta-Secretase (BACE-1) Inhibitors Showing Amyloid-beta (Abeta) Lowering in Brain.,Gravenfors Y, Viklund J, Blid J, Ginman T, Karlstrom S, Kihlstrom J, Kolmodin K, Lindstrom J, von Berg S, von Kieseritzky F, Slivo C, Swahn BM, Olsson LL, Johansson P, Eketjall S, Falting J, Jeppsson F, Stromberg K, Janson J, Rahm F J Med Chem. 2012 Oct 3. PMID:23017051^[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
↑ Gravenfors Y, Viklund J, Blid J, Ginman T, Karlstrom S, Kihlstrom J, Kolmodin K, Lindstrom J, von Berg S, von Kieseritzky F, Slivo C, Swahn BM, Olsson LL, Johansson P, Eketjall S, Falting J, Jeppsson F, Stromberg K, Janson J, Rahm F. New Aminoimidazoles as beta-Secretase (BACE-1) Inhibitors Showing Amyloid-beta (Abeta) Lowering in Brain. J Med Chem. 2012 Oct 3. PMID:23017051 doi:http://dx.doi.org/10.1021/jm300991n

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/4b1d"

@@ Line 1: / Line 1: @@
 ==New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain==
-<StructureSection load='4b1d' size='340' side='right' caption='[[4b1d]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='4b1d' size='340' side='right'caption='[[4b1d]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4b1d]] 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=4B1D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4B1D FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4b1d]] 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=4B1D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4B1D FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6TG:(2S)-2-(4-METHOXY-3,5-DIMETHYLPHENYL)-5-METHYL-2-(3-PYRIMIDIN-5-YLPHENYL)-2H-IMIDAZOL-4-AMINE'>6TG</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</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]] 1.95&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1fkn|1fkn]], [[1m4h|1m4h]], [[1py1|1py1]], [[1sgz|1sgz]], [[1tqf|1tqf]], [[1ujj|1ujj]], [[1ujk|1ujk]], [[1w50|1w50]], [[1w51|1w51]], [[1xn2|1xn2]], [[1xn3|1xn3]], [[1xs7|1xs7]], [[1ym2|1ym2]], [[1ym4|1ym4]], [[2b8l|2b8l]], [[2b8v|2b8v]], [[2fdp|2fdp]], [[2va5|2va5]], [[2va6|2va6]], [[2va7|2va7]], [[2vie|2vie]], [[2vij|2vij]], [[2viy|2viy]], [[2viz|2viz]], [[2vj6|2vj6]], [[2vj7|2vj7]], [[2vj9|2vj9]], [[2vkm|2vkm]], [[2vnm|2vnm]], [[2vnn|2vnn]], [[2wez|2wez]], [[2wf0|2wf0]], [[2wf1|2wf1]], [[2wf2|2wf2]], [[2wf3|2wf3]], [[2wf4|2wf4]], [[2wjo|2wjo]], [[2xfi|2xfi]], [[2xfj|2xfj]], [[2xfk|2xfk]], [[4acu|4acu]], [[4acx|4acx]], [[4azy|4azy]], [[4b00|4b00]], [[4b05|4b05]], [[4b0q|4b0q]], [[4b1c|4b1c]], [[4b1e|4b1e]]</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6TG:(2S)-2-(4-METHOXY-3,5-DIMETHYLPHENYL)-5-METHYL-2-(3-PYRIMIDIN-5-YLPHENYL)-2H-IMIDAZOL-4-AMINE'>6TG</scene>, <scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=4b1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1d OCA], [https://pdbe.org/4b1d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4b1d RCSB], [https://www.ebi.ac.uk/pdbsum/4b1d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1d ProSAT]</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=4b1d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4b1d OCA], [http://pdbe.org/4b1d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4b1d RCSB], [http://www.ebi.ac.uk/pdbsum/4b1d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4b1d ProSAT]</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 22: / Line 21: @@
 ==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: Berg, S]]
+[[Category: Blid J]]
-[[Category: Blid, J]]
+[[Category: Eketjall S]]
-[[Category: Eketjall, S]]
+[[Category: Falting J]]
-[[Category: Falting, J]]
+[[Category: Ginman T]]
-[[Category: Ginman, T]]
+[[Category: Gravenfors Y]]
-[[Category: Gravenfors, Y]]
+[[Category: Janson J]]
-[[Category: Janson, J]]
+[[Category: Jeppsson F]]
-[[Category: Jeppsson, F]]
+[[Category: Johansson P]]
-[[Category: Johansson, P]]
+[[Category: Karlstrom S]]
-[[Category: Karlstrom, S]]
+[[Category: Kihlstrom J]]
-[[Category: Kieseritzky, F]]
+[[Category: Kolmodin K]]
-[[Category: Kihlstrom, J]]
+[[Category: Lindstrom J]]
-[[Category: Kolmodin, K]]
+[[Category: Olsson L]]
-[[Category: Lindstrom, J]]
+[[Category: Rahm F]]
-[[Category: Olsson, L]]
+[[Category: Slivo C]]
-[[Category: Rahm, F]]
+[[Category: Stromberg K]]
-[[Category: Slivo, C]]
+[[Category: Swahn B]]
-[[Category: Stromberg, K]]
+[[Category: Viklund J]]
-[[Category: Swahn, B]]
+[[Category: Von Berg S]]
-[[Category: Viklund, J]]
+[[Category: Von Kieseritzky F]]
-[[Category: Hydrolase]]
-[[Category: Inhibitor]]
-[[Category: Lead generation]]
-[[Category: Structure-based drug design]]

4b1d

From Proteopedia

Current revision

New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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