Clermont Université, UBP, EA 987, LCHG, BP 10448, F-63000 Clermont-Ferrand, France.
Bioorg Med Chem. 2011 Jul 15;19(14):4346-54. doi: 10.1016/j.bmc.2011.05.036. Epub 2011 May 24.
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.
我们设计了双齿配体，通过两个结合位点靶向 PDZ 结构域：S0 位点，由 GLGF 环限定；S1 位点，位于β(B)/β(C)环周围的一个区域。分子对接研究使我们能够设计一个通用的 S0 结合物，其上连接一个可变大小的接头，接头本身连接到一个旨在与 PDZ 结构域的 S1 位点相互作用的氨基酸。通过在 6-11 步中以良好的总收率（24-43%）制备了一系列 15 种新型双齿配体。其中一些配体对 5-羟色胺 5-HT2A 受体/PSD-95 相互作用表现出抑制活性。这是通过使用作为诱饵的对应于受体 C 末端残基的合成十肽的下拉测定来评估的。
