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PDBsum entry 4zsp
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Hydrolase/hydrolase inhibitor
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PDB id
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4zsp
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PDB id:
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Hydrolase/hydrolase inhibitor
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Title:
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Bace crystal structure with bicyclic aminothiazine inhibitor
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Structure:
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Beta-secretase 1. Chain: a, b. Fragment: unp residues 14-454. Synonym: aspartyl protease 2,asp 2,beta-site amyloid precursor protein cleaving enzyme 1,beta-site app cleaving enzyme 1,memapsin-2, membrane-associated aspartic protease 2. Engineered: yes
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: bace1, bace, kiaa1149. Expressed in: escherichia coli. Expression_system_taxid: 562
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Resolution:
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1.91Å
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R-factor:
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0.189
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R-free:
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0.243
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Authors:
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D.E.Timm
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Key ref:
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L.L.Winneroski
et al.
(2015).
Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
Bioorg Med Chem Lett,
23,
3260-3268.
PubMed id:
DOI:
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Date:
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13-May-15
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Release date:
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10-Jun-15
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PROCHECK
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Headers
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References
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P56817
(BACE1_HUMAN) -
Beta-secretase 1 from Homo sapiens
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Seq:
Struc:
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501 a.a.
390 a.a.
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Key: |
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Secondary structure |
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CATH domain |
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DOI no:
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Bioorg Med Chem Lett
23:3260-3268
(2015)
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PubMed id:
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Preparation and biological evaluation of conformationally constrained BACE1 inhibitors.
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L.L.Winneroski,
M.A.Schiffler,
J.A.Erickson,
P.C.May,
S.A.Monk,
D.E.Timm,
J.E.Audia,
J.P.Beck,
L.N.Boggs,
A.R.Borders,
R.D.Boyer,
R.A.Brier,
K.J.Hudziak,
V.J.Klimkowski,
P.Garcia Losada,
B.M.Mathes,
S.L.Stout,
B.M.Watson,
D.J.Mergott.
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ABSTRACT
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The BACE1 enzyme is a key target for Alzheimer's disease. During our BACE1
research efforts, fragment screening revealed that bicyclic thiazine 3 had low
millimolar activity against BACE1. Analysis of the co-crystal structure of 3
suggested that potency could be increased through extension toward the S3 pocket
and through conformational constraint of the thiazine core. Pursuit of
S3-binding groups produced low micromolar inhibitor 6, which informed the
S3-design for constrained analogs 7 and 8, themselves prepared via independent,
multi-step synthetic routes. Biological characterization of BACE inhibitors 6-8
is described.
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Links
