Biased signaling in GPCRs: Structural insights and implications for drug development. Pharmacol Ther 2025 Feb;266:108786
Date
12/25/2024Pubmed ID
39719175DOI
10.1016/j.pharmthera.2024.108786Scopus ID
2-s2.0-85213279390 (requires institutional sign-in at Scopus site) 12 CitationsAbstract
G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors in humans, playing a crucial role in regulating diverse cellular processes and serving as primary drug targets. Traditional drug design has primarily focused on ligands that uniformly activate or inhibit GPCRs. However, the concept of biased agonism-where ligands selectively stabilize distinct receptor conformations, leading to unique signaling outcomes-has introduced a paradigm shift in therapeutic development. Despite the promise of biased agonists to enhance drug efficacy and minimize side effects, a comprehensive understanding of the structural and biophysical mechanisms underlying biased signaling is essential. Recent advancements in GPCR structural biology have provided unprecedented insights into ligand binding, conformational dynamics, and the molecular basis of biased signaling. These insights, combined with improved techniques for characterizing ligand efficacy, have driven the development of biased ligands for several GPCRs, including opioid, angiotensin, and adrenergic receptors. This review synthesizes these developments, from mechanisms to drug discovery in biased signaling, emphasizing the role of structural insights in the rational design of next-generation biased agonists with superior therapeutic profiles. Ultimately, these advances hold the potential to revolutionize GPCR-targeted drug discovery, paving the way for more precise and effective treatments.
Author List
Ma Y, Patterson B, Zhu LAuthor
Lan Zhu PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDrug Design
Drug Discovery
Humans
Ligands
Protein Conformation
Receptors, G-Protein-Coupled
Signal Transduction
