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Pharmacology isn’t only about ligands, receptors, and downstream G protein signaling—it’s also about The Hidden Lever in GPCR Research In GPCR pharmacology, the conversation often centers on ligand properties—affinity Why System Sensitivity Matters Consider the signaling cascade: ligand binds receptor, receptor couples The quantitative strength of this cascade depends not just on the ligand, but also on the abundance and News code) 👉   Explore Trailers & Join Today Why Terry’s Corner The pharmacology landscape is dynamic—ligands

with chemist Johannes Broichhagen aka JB, the goal was bold and elegant: Create a photo-switchable ligand Hodson: physiology, disease context, and imaging logic JB: chemistry, ligand engineering, mechanistic Collaboration, Chemistry, and the Pivot That Changed the Project Goal:  Develop a photo-switchable GPCR ligand

Allostery isn’t just an advanced concept—it’s essential to understanding efficacy, ligand bias, and receptor As the GPCR field surges forward—from ligand bias to signaling diversity—the guest editors Dr. Why you need to be there: Learn how kinetic nuance shapes ligand design.   Access peer insights on allosteric modulators and biased ligands.

Biased agonism is a phenomenon where different ligands acting on the same receptor trigger distinct signaling Biased agonism at the GLP-1R has been extensively studied, revealing that different ligands can stabilize Compared to the endogenous ligand GLP-1, another endogenous ligand, oxyntomodulin, exhibits a bias towards models have shown that although exendin-P5 induces lower insulin release compared to exendin, both ligands In contrast, ligands like oxyntomodulin that preferentially activate ERK1/2 signaling interact more significantly

  — A tale of detergent tails: GPCR activation beyond ligands .   A new commentary highlights how detergents and cholesterol shape mGluR2 activation—no ligand required

enabled selective adenosine receptor antagonists; tryptophan modifications led to somatostatin receptor ligands similarity mapping, such as SEA (Similarity Ensemble Approach), which compares the chemical similarity of ligands This reroutes discovery toward: Functionally selective ligands Better therapeutic windows More predictable favorable safety , and unique mechanisms , including GPCR modulation through agonism, internalization, or ligand

August 2022 "Genetically encoded fluorescent biosensors allow intracellular signaling dynamics to be

receptors (CKRs) that signal via Gαi and 4 official atypical chemokine receptors (ACKRs) which engage in ligand sites, while maintaining the responsiveness of canonical G protein-coupled CKRs that bind to the same ligand inflammatory response when needed; and it may interfere with other chemokine receptors which share the ligands CKRs should be considered when evaluating the safety and therapeutic efficacy of blocking receptor-ligand

High-throughput approaches used in drug discovery create large datasets regarding ligand synthesis and screening, ligand binding assays, signaling assays, cell imaging, protein structure determination, and GPCR-ligand interactions: ML can predict GPCR-ligand interactions based on input data of protein sequences One major challenge is the identification of receptor subtype-selective ligands. Paremeters such as ligand affinity for the receptor (pKi), the ability of a ligand to induce or inhibit

Predictive GPCR-Ligand Modeling Carlsson's work quickly shifted from curiosity to impact. Using virtual screening, he was able to identify novel ligands that aligned with experimental findings from commercial compound libraries, the work inevitably reaches a point where novel, non-commercial ligands His lab has already begun using AlphaFold models to identify ligands for targets that lack experimental As predictive modeling matures, its role will continue to expand, guiding ligand discovery, informing

Discover how receptors actually behave, how ligands uniquely sculpt their function, and how cryptic allosteric

In this session, you’ll gain: ✅ A mental model you can trust  for predicting how GPCR ligands behave Every ligand you design enters a system that is already balancing opposing forces—vasoconstriction vs You’ll come away asking Which of my ligands might be producing hidden signaling from inside the cell—and Ligands come and go, feedback loops kick in, and what you see in vitro rarely tells the whole story.

more nuanced, and mastering drug binding kinetics is essential for pipeline efficiency: How fast a ligand Competitive conditions —such as the presence of endogenous ligands— change kinetic behavior , and ignoring How do competing ligands slow or alter binding rates, and what does this tell you about real-world pharmacology

At a molecular level, different ligands bind to the same receptor and vice-versa (Marcuzzi et al. 2018 Drug discovery is shifting towards the development of biased ligands, which promote the engagement of Furthermore, both chemokines and receptors can homo- and hetero-oligomerize, impacting receptor/ligand-binding and signaling patterns, by modulating ligand binding, as well as G-protein coupling or interaction with , unlike most of the class A GPCRs ligands that are small molecules or short peptides.

Once a ligand crosses into this intracellular space, it behaves differently, often much more favorably Same Affinity, Different Outcomes: Why Residence Time Matters More Two ligands. And while orthosteric ligands may never reach them, properly designed intracellular drugs can.

epidermal growth factor-induced phosphorylation of Gαi at specific residues predominantly inhibits ligand-induced Key findings include: Phosphorylation Hotspots: P Loop (Ser44, Ser47, Thr48): Impairs ligand-stimulated Interdomain Cleft (Ser151, Tyr154, Tyr155): Phosphorylation at Tyr154 and Tyr155 impaired ligand-stimulated C Terminus (Tyr320): Phosphorylation at Tyr320 disrupted Gβγ binding, receptor coupling, and ligand-stimulated

A diverse pharmacopoeia of cannabinoid ligands is available, which has led to considerable advancements However, until recently, most CB2 ligands were highly lipophilic and as such not optimal for clinical A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties We review the current state of CB2 ligand development and progress in optimising physicochemical properties

protein-coupled receptors are a useful addition to the molecular pharmacology assay toolbox to characterize ligand agonism and inverse agonism on living cells in a microplate reader assay format upon stimulation with H3R ligands have further characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time and evaluating its compatibility with photopharmacological ligands that contain a ready-to-use, high-throughput alternative for radioligand binding assays that in addition can also detect ligand

A diverse pharmacopeia of cannabinoid ligands is available, which has led to considerable advancements However, until recently, most CB2 ligands were highly lipophilic and as such, not optimal for clinical A number of strategies have been applied to develop CB2 ligands to achieve closer to 'drug-like' properties We review the current state of CB2 ligand development and progress in optimizing physicochemical properties

Study of small molecule binding to live cells provides important information on the characterization of ligands coupled receptor (GPCR), we used one antagonist as probe and multiple other antagonists as competitor ligands Competition binding analysis by titration of five known ligands suggested a good correlation with their This versatile method allows quantitative characterization of ligand binding to cell surface expressed

Among the challenging GPCRs are approximately 50 that have large natural ligands. The significantly increased surface area of ligand-receptor interface for these GPCRs makes modulation These approaches include generating ligand analogs by precision engineering the natural small protein ligand of the receptor. Small protein GPCRs feature a two-component binding mechanism in which one part of the ligand engages

receptor-lipid interface represent an uncharacteristic binding location that raises many questions about the ligand Although ligand-lipid interactions are weak, lipid tails play a role in ligand binding pose stability We discuss physicochemical aspects of ligand binding at the receptor-lipid interface and suggest a compound library enriched by weak donor groups for ligand search in such sites."

Historically, ligands for GPCRs have been identified before their receptor counterparts. , several unidentified receptors have been found and were labelled as “orphan” for their endogenous ligands Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance and 2. which ligands can be used as tool compounds to study the function and biology of this receptor In addition, several GPR84 ligands have been described as well as GPR84 knockout mice.

5 to 26, 2024 What You’ll Learn during the four sessions: How to measure pharmacologic activity of ligands (affinity, efficacy, co-operativity) Determining mechanisms of action for new GPCR ligands Key elements 31, 2024 What You’ll Master during the five sessions: Utilizing new cellular assays to analyze GPCR ligand behavior Predicting activity and in vivo target coverage with real-time kinetics Discovering new ligands

the Gαi3 heterotrimers Activation/Deactivation Free-Energy Profiles for the β2-Adrenergic Receptor: Ligand ascosporogenesis in the wheat scab fungus GPCR Binders, Drugs, and more Development of Photoswitchable Tethered Ligands Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating

conformational ensemble of CX3C chemokine receptor 1 (CX3CR1) and its interactions with antagonist and agonist ligands receptor 1 (CX3CR1), a member of the class A of G Protein-Coupled Receptors (GPCR) superfamily, and its ligand characterize the conformational ensemble of the receptor in the presence of its antagonist and agonist ligands the receptor conformational changes and described interactions within its key regions and the bounded ligands

The most valuable conversations don’t happen under fluorescent lights — they happen when the ties are

De Graaf for their excellent work on Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability Molecular Insights into GPCR Function Comparative Study of Allosteric GPCR Binding Sites and Their Ligandability

November 2022 "Some G protein-coupled receptor (GPCR) ligands act as "biased agonists" that preferentially differential subcellular signaling contributes to the biased signaling generated by three endogenous ligands The signaling profile of CXCR3 changes as it traffics from the plasma membrane to endosomes in a ligand-specific

However, the impact on structure-based ligand discovery remained uncertain due to the necessity for accurately found that AF2 models achieved accurate side-chain predictions and successfully docked high-affinity ligands AlphaFold2 structures guide prospective ligand discovery.