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PDBsum entry 4lph
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Transferase/transferase inhibitor
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PDB id
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4lph
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References listed in PDB file
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Key reference
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Title
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Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.
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Authors
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J.W.De schutter,
J.Park,
C.Y.Leung,
P.Gormley,
Y.S.Lin,
Z.Hu,
A.M.Berghuis,
J.Poirier,
Y.S.Tsantrizos.
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Ref.
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J Med Chem, 2014,
57,
5764-5776.
[DOI no: ]
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PubMed id
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Abstract
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Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian
isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer
from poor "drug-like" properties and are mainly effective in treating
skeletal diseases. Recent investigations have implicated hFPPS in various
nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single
nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed
AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated
tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are
strongly implicated in AD progression. The development of nonbisphosphonate
inhibitors can provide molecular tools for validating hFPPS as a therapeutic
target for tauopathy-associated neurodegeneration. A multistage screening
protocol led to the identification of a new monophosphonate chemotype that bind
in an allosteric pocket of hFPPS. Optimization of these compounds could lead to
human therapeutics that block tau metabolism and arrest the progression of
neurodegeneration.
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