Molecular Glues: A New Approach to Modulating GPCR Signaling Bias DOI Creative Commons

Jamie Kushnir,

Ryan H. Gumpper

Biochemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

G-protein-coupled receptors (GPCRs) transmit an extracellular chemical/biological signal across the cell membrane, stimulating array of intracellular signaling cascades. Canonically, these molecules bind to endogenous ligand pocket (orthosteric pocket), which stabilizes either active or inactive conformational ensemble receptor. However, recent structural evidence indicates that small can mediate protein–protein interactions between GPCR and their transducers. These are reminiscent molecular glues be powerful tools for modulating bias. In this Perspective, we will investigate current information available on how they modulate We also examine prospects drug/probe design.

Language: Английский

G protein-coupled receptors (GPCRs): advances in structures, mechanisms and drug discovery DOI Creative Commons
Mingyang Zhang, Ting Chen, Xun Lu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 9, 2024

Abstract G protein-coupled receptors (GPCRs), the largest family of human membrane proteins and an important class drug targets, play a role in maintaining numerous physiological processes. Agonist or antagonist, orthosteric effects allosteric effects, biased signaling balanced signaling, characterize complexity GPCR dynamic features. In this study, we first review structural advancements, activation mechanisms, functional diversity GPCRs. We then focus on discovery by revealing detailed drug-target interactions underlying mechanisms drugs approved US Food Drug Administration past five years. Particularly, up-to-date analysis is performed available structures complexed with synthetic small-molecule modulators to elucidate key receptor-ligand mechanisms. Finally, highlight how widespread GPCR-druggable sites can guide structure- mechanism-based design propose prospects designing bitopic ligands for future therapeutic potential targeting receptor family.

Language: Английский

Citations

104
Direct interrogation of context-dependent GPCR activity with a universal biosensor platform DOI Creative Commons
Remi Janicot,

Marcin Maziarz,

Jong‐Chan Park

et al.

Cell, Journal Year: 2024, Volume and Issue: 187(6), P. 1527 - 1546.e25

Published: Feb. 26, 2024

Language: Английский

Citations

21
Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery DOI Creative Commons
Paolo Conflitti, Edward Lyman, Mark S.P. Sansom

et al.

Nature Reviews Drug Discovery, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Language: Английский

Citations

3
A cryptic pocket in CB1 drives peripheral and functional selectivity DOI
Vipin Ashok Rangari, Evan S. O’Brien,

Alexander S. Powers

et al.

Nature, Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

Language: Английский

Citations

2
Molecular basis of opioid receptor signaling DOI Creative Commons
Tao Che, Bryan L. Roth

Cell, Journal Year: 2023, Volume and Issue: 186(24), P. 5203 - 5219

Published: Nov. 1, 2023

Language: Английский

Citations

37
Structure, function and drug discovery of GPCR signaling DOI Creative Commons
Lin Cheng, Fan Xia, Ziyan Li

et al.

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Dec. 4, 2023

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes responses, such as sensory perception (e.g., vision, taste, smell), immune response, hormone regulation, neurotransmission. Their diverse essential roles the body make them significant focus for pharmaceutical research drug development. Currently, approximately 35% marketed drugs directly target GPCRs, underscoring their prominence therapeutic targets. Recent advances structural biology have substantially deepened our understanding GPCR activation mechanisms interactions with G-protein arrestin signaling pathways. This review offers an in-depth exploration both traditional recent methods structure analysis. It presents structure-based insights into ligand recognition receptor delves deeper canonical noncanonical pathways downstream GPCRs. Furthermore, it highlights advancements GPCR-related discovery Particular emphasis is placed on selective drugs, allosteric biased signaling, polyphamarcology, antibody drugs. Our goal to provide researchers thorough updated determination, pathway investigation, foundation aims propel forward-thinking approaches that drawing upon latest selectivity, activation, mechanisms.

Language: Английский

Citations

32
A µ-opioid receptor modulator that works cooperatively with naloxone DOI
Evan S. O’Brien, Vipin Ashok Rangari,

Amal El Daibani

et al.

Nature, Journal Year: 2024, Volume and Issue: 631(8021), P. 686 - 693

Published: July 3, 2024

Language: Английский

Citations

14
In Vitro Functional Profiling of Fentanyl and Nitazene Analogs at the μ-Opioid Receptor Reveals High Efficacy for Gi Protein Signaling DOI
Meng-Hua M. Tsai, Li Chen, Michael H. Baumann

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: 15(4), P. 854 - 867

Published: Feb. 12, 2024

Novel synthetic opioids (NSOs), including both fentanyl and non-fentanyl analogs that act as μ-opioid receptor (MOR) agonists, are associated with serious intoxication fatal overdose. Previous studies proposed G-protein-biased MOR agonists safer pain medications, while other evidence indicates low intrinsic efficacy at better explains the reduced opioid side effects. Here, we characterized in vitro functional profiles of various NSOs using adenylate cyclase inhibition β-arrestin2 recruitment assays, conjunction application depletion approach. By fitting concentration–response data to operational model agonism, deduced affinity for each Gi protein signaling pathways. Compared reference agonist [d-Ala2,N-MePhe4,Gly-ol5]enkephalin, found several were more efficacious inhibiting cAMP production, whereas all less recruiting β-arrestin2. In contrast, 2-benzylbenzimidazole (i.e., nitazene) highly potent assays. Our findings suggest high is a common property may underlie their risk overdose, highlighting limitation bias predict adverse effects opioids. addition, extremely potency many now infiltrating illicit drug markets further contributes danger posed public health.

Language: Английский

Citations

9
Molecular dynamics-based identification of binding pathways and two distinct high-affinity sites for succinate in succinate receptor 1/GPR91 DOI Creative Commons

Aslihan Shenol,

Michael Lückmann, Mette Trauelsen

et al.

Molecular Cell, Journal Year: 2024, Volume and Issue: 84(5), P. 955 - 966.e4

Published: Feb. 6, 2024

SUCNR1 is an auto- and paracrine sensor of the metabolic stress signal succinate. Using unsupervised molecular dynamics (MD) simulations (170.400 ns) mutagenesis across human, mouse, rat SUCNR1, we characterize how a five-arginine motif around extracellular pole TM-VI determines initial capture succinate in vestibule (ECV) to either stay or move down orthosteric site. Metadynamics demonstrate low-energy binding both sites, with energy barrier corresponding intermediate stage during which succinate, associated water cluster, unlocks hydrogen-bond-stabilized conformationally constrained loop (ECL)-2b. Importantly, simultaneous two molecules through "sequential" "bypassing" mode frequent endpoint. The mono-carboxylate NF-56-EJ40 antagonist enters between TM-I -II does not unlock ECL-2b. It proposed that occupancy high-affinity sites required for selective activation by high local concentrations.

Language: Английский

Citations

8
AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine–associated receptor 1 DOI Creative Commons
Alejandro Díaz‐Holguín, Marcus Saarinen,

Duc Duy Vo

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(32)

Published: Aug. 7, 2024

Artificial intelligence is revolutionizing protein structure prediction, providing unprecedented opportunities for drug design. To assess the potential impact on ligand discovery, we compared virtual screens using structures generated by AlphaFold machine learning method and traditional homology modeling. More than 16 million compounds were docked to models of trace amine-associated receptor 1 (TAAR1), a G protein-coupled unknown target treating neuropsychiatric disorders. Sets 30 32 highly ranked from model screens, respectively, experimentally evaluated. Of these, 25 TAAR1 agonists with potencies ranging 12 0.03 μM. The screen yielded more twofold higher hit rate (60%) discovered most potent agonists. A agonist promising selectivity profile drug-like properties showed physiological antipsychotic-like effects in wild-type but not knockout mice. These results demonstrate that can accelerate discovery.

Language: Английский

Citations

8