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PDBsum entry 3vv8
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Hydrolase/hydrolase inhibitor
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PDB id
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3vv8
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References listed in PDB file
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Key reference
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Title
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Conformational restriction approach to β-Secretase (bace1) inhibitors: effect of a cyclopropane ring to induce an alternative binding mode.
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Authors
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S.Yonezawa,
T.Yamamoto,
H.Yamakawa,
C.Muto,
M.Hosono,
K.Hattori,
K.Higashino,
T.Yutsudo,
H.Iwamoto,
Y.Kondo,
M.Sakagami,
H.Togame,
Y.Tanaka,
T.Nakano,
H.Takemoto,
M.Arisawa,
S.Shuto.
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Ref.
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J Med Chem, 2012,
55,
8838-8858.
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PubMed id
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Abstract
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Improvement of a drug's binding activity using the conformational restriction
approach with sp(3) hybridized carbon is becoming a key strategy in drug
discovery. We applied this approach to BACE1 inhibitors and designed four
stereoisomeric cyclopropane compounds in which the ethylene linker of a known
amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The
synthesis and biologic evaluation of these compounds revealed that the
cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among
them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its
unique binding mode is due to the apparent CH-π interaction between the rigid
cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a
lead molecule led to the development of highly potent inhibitors in which the
structure-activity relationship as well as the binding mode of the compounds
clearly differ from those of known amidine-type inhibitors.
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