5he4: Difference between revisions
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==BACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium== | ==BACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium== | ||
<StructureSection load='5he4' size='340' side='right' caption='[[5he4]], [[Resolution|resolution]] 1.53Å' scene=''> | <StructureSection load='5he4' size='340' side='right'caption='[[5he4]], [[Resolution|resolution]] 1.53Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5he4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5HE4 OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5he4]] is a 2 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=5HE4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5HE4 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=60T:(2E,4AR,7AS)-7A-(2,6-DIFLUOROPHENYL)-6-(5-FLUORO-4-METHOXY-6-METHYLPYRIMIDIN-2-YL)-2-IMINO-3-METHYLOCTAHYDRO-4H-PYRROLO[3,4-D]PYRIMIDIN-4-ONE'>60T</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=60T:(2E,4AR,7AS)-7A-(2,6-DIFLUOROPHENYL)-6-(5-FLUORO-4-METHOXY-6-METHYLPYRIMIDIN-2-YL)-2-IMINO-3-METHYLOCTAHYDRO-4H-PYRROLO[3,4-D]PYRIMIDIN-4-ONE'>60T</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5he5|5he5]], [[5hdz|5hdz]], [[5hdx|5hdx]], [[5hdv|5hdv]], [[5hdu|5hdu]], [[5he7|5he7]], [[5hd0|5hd0]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5he5|5he5]], [[5hdz|5hdz]], [[5hdx|5hdx]], [[5hdv|5hdv]], [[5hdu|5hdu]], [[5he7|5he7]], [[5hd0|5hd0]]</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='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:// | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5he4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5he4 OCA], [http://pdbe.org/5he4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5he4 RCSB], [http://www.ebi.ac.uk/pdbsum/5he4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5he4 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5he4" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5he4" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Memapsin 2]] | [[Category: Memapsin 2]] | ||
[[Category: Orth, P]] | [[Category: Orth, P]] | ||
[[Category: | [[Category: Alzheimerss']] | ||
[[Category: Aspartyl protease]] | [[Category: Aspartyl protease]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 10:01, 20 May 2020
BACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminiumBACE-1 in complex with (4aR,7aS)-7a-(2,6-difluorophenyl)-6-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium
Structural highlights
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 PubMedWe describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2 pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Abeta40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Abeta in nonrodent preclinical species. Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central Abeta in Nonhuman Primates.,Mandal M, Wu Y, Misiaszek J, Li G, Buevich A, Caldwell JP, Liu X, Mazzola RD, Orth P, Strickland C, Voigt J, Wang H, Zhu Z, Chen X, Grzelak M, Hyde LA, Kuvelkar R, Leach PT, Terracina G, Zhang L, Zhang Q, Michener MS, Smith B, Cox K, Grotz D, Favreau L, Mitra K, Kazakevich I, McKittrick BA, Greenlee W, Kennedy ME, Parker EM, Cumming JN, Stamford AW J Med Chem. 2016 Apr 14;59(7):3231-48. doi: 10.1021/acs.jmedchem.5b01995. Epub, 2016 Mar 22. PMID:26937601[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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