Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery
| Autor: | Marc G. Caron, Larry S. Barak, Lauren M. Slosky |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pharmacology Drug discovery Allosteric regulation Computational biology Biology Ligands Toxicology Article Receptors G-Protein-Coupled Receptor subtype 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Allosteric Regulation Drug development Cell surface receptor Drug Discovery Functional selectivity Receptor 030217 neurology & neurosurgery Signal Transduction G protein-coupled receptor |
| Zdroj: | Trends Pharmacol Sci |
| ISSN: | 0165-6147 |
| DOI: | 10.1016/j.tips.2020.12.005 |
| Popis: | G protein-coupled receptors (GPCRs) are the largest class of cell surface receptors in the genome and the most successful family of targets of FDA-approved drugs. New frontiers in GPCR drug discovery remain, however, as achieving receptor subtype selectivity and controlling off- and on-target side effects are not always possible with classic agonist and antagonist ligands. These challenges may be overcome by focusing development efforts on allosteric ligands that confer signaling bias. Biased allosteric modulators (BAMs) are an emerging class of GPCR ligands that engage less well-conserved regulatory motifs outside the orthosteric pocket and exert pathway-specific effects on receptor signaling. The unique ways that BAMs texturize receptor signaling present opportunities to fine-tune physiology and develop safer, more selective therapeutics. Here, we provide a conceptual framework for understanding the pharmacology of BAMs, explore their therapeutic potential, and discuss strategies for their discovery. |
| Databáze: | OpenAIRE |
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