The Potential of 19F NMR Application in GPCR Biased Drug Discovery

Studies indicate that G protein-coupled receptor (GPCR) activation is a multistate transition process instead of a simple switch, suggesting the possibility of modulating the GPCR function through tuning of these individual states. A biased ligand was proposed to specifically target one signaling pathway over others in a multiple-signaling coexistence system. However, despite the progress in structural biology, a detailed mechanism of how this is achieved remains elusive. Research has indicated that different GPCR conformations interact with different downstream partners, dictating various pharmacological outputs. 19F NMR has been demonstrated to be extremely promising in delineating GPCR conformations, attributable to its quantitative properties and high sensitivity toward electrostatic changes of the probe microenvironment. Thus, there is tremendous potential for biased drug discovery by establishing a rigorous correlation between individual receptor conformations and the pharmacological consequence upon ligand binding. Although structure-based virtual drug discovery is revolutionizing the conventional high-throughput cell-based screening system, its limitation is obvious, together with other critical challenges. In particular, the resolved static snapshots fail to represent a full free-energy landscape due to homogenization in structural determination processing. The loss of conformational heterogeneity and related functional diversity emphasize the necessity of developing an approach that can fill this space. In this regard, NMR holds undeniable potential. However, outstanding questions regarding the NMR application remain. This review summarizes the limitations of current drug discovery and explores the potential of 19F NMR in establishing a conformation-guided drug screening system, advancing the cell- and structure-based discovery strategy for G protein-coupled receptor (GPCR) biased drug screening. Although structure-based virtual drug discovery is revolutionizing the conventional high-throughput cell-based screening system, its limitation is obvious, together with other critical challenges. In particular, the resolved static snapshots fail to represent a full free-energy landscape due to homogenization in structural determination processing. The loss of conformational heterogeneity and related functional diversity emphasize the necessity of developing an approach that can fill this space. In this regard, NMR holds undeniable potential. However, outstanding questions regarding the NMR application remain. This review summarizes the limitations of current drug discovery and explores the potential of 19F NMR in establishing a conformation-guided drug screening system, advancing the cell- and structure-based discovery strategy for G protein-coupled receptor (GPCR) biased drug screening. a drug that increases activities of multiple signaling pathways. a drug that increases the activity of a specific signaling pathway. a procedure that deep-freezes a sample and uses electrons to make an image of protein structure. a class of seven-transmembrane proteins that transmit extracellular to intracellular signals and are triggered by a wide range of factors, including light, compounds, peptides, and proteins. nuclear magnetic resonance, a spectrometer used for studying the behavior of different nuclei, such as 1H, 13C, 15N, and 19F, etc. an NMR technique whereby paramagnetic ions such Mn2+ are introduced to a system in order to enhance the relaxation of spins in the proximity. an additional nuclear chemical shift effect on a nucleus in spatial vicinity due to partial polarization. a technique of using X-rays passing through crystallized proteins to determine structures.