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PDBsum entry 4ngt
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Hydrolase/hydrolase inhibitor
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PDB id
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4ngt
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References listed in PDB file
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Key reference
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Title
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Rational design of urea-Based glutamate carboxypeptidase ii (gcpii) inhibitors as versatile tools for specific drug targeting and delivery.
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Authors
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J.Tykvart,
J.Schimer,
J.Bařinková,
P.Pachl,
L.Poštová-Slavětínská,
P.Majer,
J.Konvalinka,
P.ŠÁcha.
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Ref.
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Bioorg Med Chem, 2014,
22,
4099-4108.
[DOI no: ]
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PubMed id
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Abstract
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Glutamate carboxypeptidase II (GCPII), also known as prostate specific membrane
antigen (PSMA), is an established prostate cancer marker and is considered a
promising target for specific anticancer drug delivery. Low-molecular-weight
inhibitors of GCPII are advantageous specific ligands for this purpose. However,
they must be modified with a linker to enable connection of the ligand with an
imaging molecule, anticancer drug, and/or nanocarrier. Here, we describe a
structure-activity relationship (SAR) study of GCPII inhibitors with linkers
suitable for imaging and drug delivery. Structure-assisted inhibitor design and
targeting of a specific GCPII exosite resulted in a 7-fold improvement in Ki
value compared to the parent structure. X-ray structural analysis of the
inhibitor series led to the identification of several inhibitor binding modes.
We also optimized the length of the inhibitor linker for effective attachment to
a biotin-binding molecule and showed that the optimized inhibitor could be used
to target nanoparticles to cells expressing GCPII.
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