4h1e: Difference between revisions

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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
<table><tr><td colspan='2'>[[4h1e]] is a 2 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=4H1E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H1E FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</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]] 1.9&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=10J:3-{5-[(2E,4AR,7AR)-6-BENZOYL-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>10J</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [https://pdbe.org/4h1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [https://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e ProSAT]</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=4h1e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h1e OCA], [https://pdbe.org/4h1e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h1e RCSB], [https://www.ebi.ac.uk/pdbsum/4h1e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h1e ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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>  
[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 ==
On the basis of our observation that the biaryl substituent of iminopyrimidinone 7 must be in a pseudoaxial conformation to occupy the contiguous S1-S3 subsites of BACE1, we have designed a novel fused bicyclic iminopyrimidinone scaffold intended to favor this bioactive conformation. Strategic incorporation of a nitrogen atom in the new constrained ring allowed us to develop SAR around the S2' binding pocket and ultimately resulted in analogues with low nanomolar potency for BACE1. In particular, optimization of the prime side substituent led to major improvements in potency by displacement of two conserved water molecules from a region near S2'. Further optimization of the pharmacokinetic properties of this fused pyrrolidine series, in conjunction with facile access to a rat pharmacodynamic model, led to identification of compound 43, which is an orally active, brain penetrant inhibitor that reduces Abeta(40) in the plasma, CSF, and cortex of rats in a dose-dependent manner.
Design and Validation of Bicyclic Iminopyrimidinones As Beta Amyloid Cleaving Enzyme-1 (BACE1) Inhibitors: Conformational Constraint to Favor a Bioactive Conformation.,Mandal M, Zhu Z, Cumming JN, Liu X, Strickland C, Mazzola RD, Caldwell JP, Leach P, Grzelak M, Hyde L, Zhang Q, Terracina G, Zhang L, Chen X, Kuvelkar R, Kennedy ME, Favreau L, Cox K, Orth P, Buevich A, Voigt J, Wang H, Kazakevich I, McKittrick BA, Greenlee W, Parker EM, Stamford AW J Med Chem. 2012 Oct 1. PMID:22989333<ref>PMID:22989333</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4h1e" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Revision as of 16:01, 14 March 2024

Structure of BACE-1 Bound to (7aR)-6-benzoyl-7a-(4-(3-cyanophenyl)thiophen-2-yl)-3-methyl-4-oxohexahydro-1H-pyrrolo[3,4-d]pyrimidin-2(3H)-iminium

4h1e, resolution 1.90Å

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