期刊
CURRENT PHARMACEUTICAL DESIGN
卷 15, 期 6, 页码 719-729出版社
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161209787315602
关键词
Bivalent ligands; GPCR oligomers; drug design; 5-HT4 receptors; molecular modeling; organic synthesis; BRET screening
资金
- Ministere de l'Enseignement Superieur et de la Recherche, Servier
- Fondation pour la Recherche Medicale (Equipes FRM)
- Fondation pour la Recherche sur le Cerveau ( FRC) Neurodon
- Institut National de la Sante et de la Recherche Medicale ( INSERM)
- Centre National de la Recherche Scientifique ( CNRS)
Historically treated as monomeric polypeptides, G protein-coupled receptors (GPCRs) have been shown to exist and function as constitutively formed dimers or oligomers. The quaternary structure of GPCRs may modulate ligand binding properties through allosteric mechanisms offering new opportunities for drug design by exploiting multivalency. In this context, multivalent ligands versus bivalent-ligands, possessing two binding motifs connected by a linker, have been investigated and have revealed striking differences in their functional properties compared to their monovalent counterparts. These bi-functional drugs, which are able to activate the two protomers in a dimer simultaneously, emerge as novel and promising drugs for a variety of multi-factorial diseases. In this review, key requirements for the successful design and synthesis of GPCR multivalent ligands composed of pharmacophores and a linker will be discussed. We will then focus on the 5-HT4 receptor (5-HT4R), whose ligands emerged as promising drugs for a variety of central nervous disorders. Upon description of biochemical and biophysical evidences of 5-HT4R dimerization, we will present the multivalent ligand approach, which was assisted by molecular docking experiments on the 5-HT4R dimer model.
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