5clm: Difference between revisions

Revision as of 12:13, 14 June 2023

1,4-Oxazine BACE1 inhibitors

Structural highlights

5clm 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:	52K, CL, IOD
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

1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa whilst optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active and which demonstrated robust lowering of Abeta levels in vivo in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE inhibitors for the treatment of Alzheimer's Disease.

1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads.,Rombouts FJ, Tresadern G, Delgado O, Martinez Lamenca C, Van Gool M, Garcia-Molina A, Alonso De Diego SA, Oehlrich D, Prokopcova H, Alonso JM, Austin N, Borghys H, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Alexander R, Macdonald GJ, Moechars D, Gijsen HJ, Trabanco AA J Med Chem. 2015 Sep 17. PMID:26378740^[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
↑ Rombouts FJ, Tresadern G, Delgado O, Martinez Lamenca C, Van Gool M, Garcia-Molina A, Alonso De Diego SA, Oehlrich D, Prokopcova H, Alonso JM, Austin N, Borghys H, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Alexander R, Macdonald GJ, Moechars D, Gijsen HJ, Trabanco AA. 1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J Med Chem. 2015 Sep 17. PMID:26378740 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b01101

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] Rombouts FJ, Tresadern G, Delgado O, Martinez Lamenca C, Van Gool M, Garcia-Molina A, Alonso De Diego SA, Oehlrich D, Prokopcova H, Alonso JM, Austin N, Borghys H, Van Brandt S, Surkyn M, De Cleyn M, Vos A, Alexander R, Macdonald GJ, Moechars D, Gijsen HJ, Trabanco AA. 1,4-Oxazine beta-secretase (BACE1) inhibitors: from hit generation to orally bioavailable brain penetrant leads. J Med Chem. 2015 Sep 17. PMID:26378740 doi:https://dx.doi.org/10.1021/acs.jmedchem.5b01101

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='5clm' size='340' side='right'caption='[[5clm]], [[Resolution|resolution]] 2.61&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5clm]] 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=5CLM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CLM FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5clm]] 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=5CLM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CLM FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=52K:N-{3-[(3R)-5-AMINO-3-METHYL-3,6-DIHYDRO-2H-1,4-OXAZIN-3-YL]PHENYL}-5-CHLOROPYRIDINE-2-CARBOXAMIDE'>52K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=52K:N-{3-[(3R)-5-AMINO-3-METHYL-3,6-DIHYDRO-2H-1,4-OXAZIN-3-YL]PHENYL}-5-CHLOROPYRIDINE-2-CARBOXAMIDE'>52K</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</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=5clm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5clm OCA], [https://pdbe.org/5clm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5clm RCSB], [https://www.ebi.ac.uk/pdbsum/5clm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5clm 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>
-<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=5clm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5clm OCA], [http://pdbe.org/5clm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5clm RCSB], [http://www.ebi.ac.uk/pdbsum/5clm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5clm 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 27: / Line 25: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Memapsin 2]]
+[[Category: Alexander R]]
-[[Category: Alexander, R]]
+[[Category: Alonso De Diego S]]
-[[Category: Alonso, J M]]
+[[Category: Alonso JM]]
-[[Category: Austin, N]]
+[[Category: Austin N]]
-[[Category: Borghys, H]]
+[[Category: Borghys H]]
-[[Category: Brandt, S Van]]
+[[Category: De Cleyn M]]
-[[Category: Cleyn, M De]]
+[[Category: Delgado O]]
-[[Category: Delgado, O]]
+[[Category: Garcia-Molina A]]
-[[Category: Diego, S Alonso De]]
+[[Category: Gijsen H]]
-[[Category: Garcia-Molina, A]]
+[[Category: MacDonald G]]
-[[Category: Gijsen, H]]
+[[Category: Martinez Lamenca C]]
-[[Category: Gool, M Van]]
+[[Category: Moechars D]]
-[[Category: Lamenca, C Martinez]]
+[[Category: Oehlrich D]]
-[[Category: MacDonald, G]]
+[[Category: Prokopcova H]]
-[[Category: Moechars, D]]
+[[Category: Rombouts F]]
-[[Category: Oehlrich, D]]
+[[Category: Surkyn M]]
-[[Category: Prokopcova, H]]
+[[Category: Trabanco A]]
-[[Category: Rombouts, F]]
+[[Category: Tresadern G]]
-[[Category: Surkyn, M]]
+[[Category: Van Brandt S]]
-[[Category: Trabanco, A]]
+[[Category: Van Gool M]]
-[[Category: Tresadern, G]]
+[[Category: Vos A]]
-[[Category: Vos, A]]
-[[Category: Bace1 protease inhibitor]]
-[[Category: Brain penetrant]]
-[[Category: Hydrolase]]
-[[Category: Orally bioavailable]]
-[[Category: Proteros biostructures gmbh]]

5clm: Difference between revisions

Revision as of 12:13, 14 June 2023

1,4-Oxazine BACE1 inhibitors

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Navigation menu

Page actions

Page actions

Personal tools

Navigation

Search

Tools