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PDBsum entry 1ym2
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Hydrolase/hydrolase inhibitor
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PDB id
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1ym2
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References listed in PDB file
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Key reference
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Title
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Structure-Based design, Synthesis, And memapsin 2 (bace) inhibitory activity of carbocyclic and heterocyclic peptidomimetics.
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Authors
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S.Hanessian,
H.Yun,
Y.Hou,
G.Yang,
M.Bayrakdarian,
E.Therrien,
N.Moitessier,
S.Roggo,
S.Veenstra,
M.Tintelnot-Blomley,
J.M.Rondeau,
C.Ostermeier,
A.Strauss,
P.Ramage,
P.Paganetti,
U.Neumann,
C.Betschart.
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Ref.
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J Med Chem, 2005,
48,
5175-5190.
[DOI no: ]
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PubMed id
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Abstract
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Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh
heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a
series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1
spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of
the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent
truncated analogue 5 with good selectivity over Cathepsin D. Using the same
backbone replacement concept, a series of cyclopentane, cyclopentanone,
tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with
considerable variation at the P and P' sites. The cyclopentanone and
2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray
cocrystal structures of two analogues 5 and 45 revealed excellent convergence
with the original inhibitor 1 structure while providing new insights into other
interactions which could be exploited for future modifications.
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