Abstract
We designed bidentate ligands to target PDZ domains through two binding sites: site S0, delimited by the GLGF loop, and site S1, a zone situated around loop β(B)/β(C). A molecular docking study allowed us to design a generic S0 binder, to which was attached a variable size linker, itself linked to an amino acid aimed to interact with the S1 site of PDZ domains. A series of 15 novel bidentate ligands was prepared in 6-11 steps in good overall yield (24-43%). Some of these ligands showed an inhibitory activity against serotonin 5-HT2A receptor/PSD-95 interaction. This was assessed by pull-down assay using a synthetic decapeptide corresponding to the C-terminal residues of the receptor as a bait.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites / drug effects
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Computational Biology
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Disks Large Homolog 4 Protein
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Drug Design*
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Intracellular Signaling Peptides and Proteins / chemistry
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Ligands
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Membrane Proteins / antagonists & inhibitors*
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Membrane Proteins / chemistry
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Models, Molecular
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Molecular Conformation
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PDZ Domains / drug effects*
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Receptor, Serotonin, 5-HT2A / chemistry
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Receptor, Serotonin, 5-HT2A / metabolism
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Serotonin 5-HT2 Receptor Agonists / chemical synthesis
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Serotonin 5-HT2 Receptor Agonists / chemistry
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Serotonin 5-HT2 Receptor Agonists / pharmacology*
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Stereoisomerism
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Structure-Activity Relationship
Substances
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DLG4 protein, human
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Disks Large Homolog 4 Protein
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Intracellular Signaling Peptides and Proteins
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Ligands
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Membrane Proteins
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Receptor, Serotonin, 5-HT2A
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Serotonin 5-HT2 Receptor Agonists