5hdu: Difference between revisions
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==BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium== | |||
<StructureSection load='5hdu' size='340' side='right'caption='[[5hdu]], [[Resolution|resolution]] 1.58Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5hdu]] 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=5HDU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HDU FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.58Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=60W:3-{5-[(2E,4AR,7AR)-6-(5-FLUORO-4-METHOXYPYRIMIDIN-2-YL)-2-IMINO-3-METHYL-4-OXOOCTAHYDRO-7AH-PYRROLO[3,4-D]PYRIMIDIN-7A-YL]THIOPHEN-3-YL}BENZONITRILE'>60W</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=5hdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hdu OCA], [https://pdbe.org/5hdu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hdu RCSB], [https://www.ebi.ac.uk/pdbsum/5hdu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hdu ProSAT]</span></td></tr> | |||
</table> | |||
== 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> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We 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<ref>PMID:26937601</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Orth | <div class="pdbe-citations 5hdu" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta secretase 3D structures|Beta secretase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Orth P]] | |||
Latest revision as of 10:32, 9 August 2023
BACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminiumBACE-1 incomplex with (7aR)-7a-(4-(3-cyanophenyl)thiophen-2-yl)-6-(5-fluoro-4-methoxypyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium
Structural highlights
FunctionBACE1_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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