Covalent allosteric modulation: An emerging strategy for GPCRs drug discovery
| Autor: | Jacob Cuyler, Xiang-Qun Xie, Jaden Jungho Jun, Yuemin Bian |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Allosteric modulator
Allosteric regulation Covalent binding 01 natural sciences Article Receptors G-Protein-Coupled 03 medical and health sciences Allosteric Regulation Drug Discovery Animals Humans 030304 developmental biology G protein-coupled receptor Pharmacology 0303 health sciences Binding Sites 010405 organic chemistry Drug discovery Chemistry Organic Chemistry General Medicine 0104 chemical sciences Structural biology Covalent bond Metabotropic glutamate receptor Biophysics |
| Zdroj: | Eur J Med Chem |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2020.112690 |
| Popis: | Designing covalent allosteric modulators brings new opportunities to the field of drug discovery towards G-protein-coupled receptors (GPCRs). Targeting an allosteric binding pocket can allow a modulator to have protein subtype selectivity and low drug resistance. Utilizing covalent warheads further enables the modulator to increase the binding potency and extend the duration of action. This review starts with GPCR allosteric modulation to discuss the structural biology of allosteric binding pockets, the different types of allosteric modulators, as well as the advantages of employing allosteric modulation. This is followed by a discussion on covalent modulators to clarify how covalent ligands can benefit the receptor modulation and to illustrate moieties that can commonly be used as covalent warheads. Finally, case studies are presented on designing class A, B, and C GPCR covalent allosteric modulators to demonstrate successful stories on combining allosteric modulation and covalent binding. Limitations and future perspectives are also covered. |
| Databáze: | OpenAIRE |
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