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Tim De Groof! It’s not often when you get the best of both worlds - nano-bodies and #GPCRs.

April 2022 Ono Enters into Collaboration Agreement with Domain Therapeutics and Université de Montréal (Strasbourg, France; CEO: Pascal Neuville; “Domain”) and Université de Montréal (Québec, Canada; “UdM

the Department of Biochemistry and Molecular Medicine of the Faculty of Medicine of the Université de

Before the advent of AlphaFold, homology modeling was the most common method for predicting G protein-coupled receptor (GPCR) structures, especially when experimental data were limited. Homology modeling relies on using the known structure of a homologous protein as a template to model the target protein ( Carlsson, J. et al., 2011 ). However, this method has limitations: its accuracy is heavily dependent on the availability and quality of the template structure. For proteins with low sequence similarity to available templates, homology models tend to be less accurate, a notable challenge for GPCRs. GPCRs are dynamic, switching between multiple conformations, and many have only distant homologs with resolved structures, making accurate predictions difficult. The introduction of AlphaFold2 marked a major advancement in the field of GPCR structure prediction. AlphaFold2 uses an AI-driven approach that eliminates the need for structural templates, allowing it to predict structures for GPCRs that were previously difficult to model due to their low sequence homology to known structures. In a recent study on TAAR1, a GPCR linked to central nervous system disorders, researchers compared the performance of AlphaFold and homology models in virtual screening efforts (Diaz-Holguin, A. et al., 2024). The results were striking: AlphaFold2 outperformed homology models, achieving a 60% hit rate for compounds targeting TAAR1, more than double that of the homology models. The AlphaFold-predicted models revealed distinct ligand-binding site shapes, enabling the prioritization of different chemotypes during docking. One of the identified TAAR1 agonists demonstrated promising antipsychotic-like effects in rodent models, reinforcing the value of AlphaFold in drug discovery, especially when experimental structures are unavailable. While AlphaFold2’s ability to predict static structures was groundbreaking, however, GPCRs are highly dynamic proteins and continuously adopt different conformations based on their interactions with ligands and the cellular environment which are crucial for understanding how drugs can selectively target different receptor conformations to achieve therapeutic effects. AlphaFold3, the latest version, has improved on this by modeling interactions with various compounds, including natural ligands, ions, DNA, and RNA. However, AlphaFold3 faces challenges with synthetic ligands, which are central to pharmaceutical development. It excels in modeling interactions with natural ligands but struggles to generalize this accuracy to synthetic compounds, limiting its utility in drug discovery involving novel drug-like molecules. While AlphaFold provides an excellent foundation for generating hypotheses in drug discovery, it is not a standalone solution. To fully understand GPCR behavior and optimize drug targeting across multiple receptor states, experimental validation such as X-ray crystallography, cryo-EM or NMR are still essential for confirming predictions, refining models, and exploring the functional states of GPCRs. Additional kinetic validations must also be verified to comprehend the functions of the proteins. Future iterations of AlphaFold, or its integration with other computational techniques, could help overcome these limitations, leading to more comprehensive models that bridge the gap between computational predictions and real-world data. References: Carlsson, J.  et al.  Ligand discovery from a dopamine D3 receptor homology model and crystal structure. Nat Chem Biol   7 , 769-778 (2011).   https://doi.org/10.1038/nchembio.662 Diaz-Holguin, A.  et al.  AlphaFold accelerated discovery of psychotropic agonists targeting the trace amine-associated receptor 1. Sci Adv   10 , eadn1524 (2024).   https://doi.org/10.1126/sciadv.adn1524

Understanding the Connection Between Residence Time and Drug Efficacy: The Importance of Moving Beyond If your lead compounds look perfect on paper but disappoint in vivo, residence time may be the missing In a world of fluctuating drug levels, residence time becomes the true predictor of effect. Residence time provides a second dimension of drug evaluation , one that explains results in animal models Unlock “Target Residence Time” Now Only in Terry’s Corner Why Terry’s Corner In a world where drug discovery

What is Homogeneous Time-Resolved Fluorescence (HTRF)? transfer between a donor and an acceptor fluorophore, and in HTRF a delay is introduced between the time Principle of time-resolved detection. Source: Nørskov-Lauritsen L, Thomsen AR, Bräuner-Osborne H. G protein-coupled receptor signaling analysis using homogenous time-resolved Förster resonance energy Signal interferences are kept to a minimum thanks to the timing of detection.

This week, you will learn how to confirm equilibrium the right way, detect time-dependent occupancy and Avoid expensive mirages:  Spot when “good” equilibrium curves mask time-dependent binding that will fail It’s built for the GPCR community—by people who live the science—so you spend less time sifting and more time deciding. If you need to brief leadership, plan experiments, or time a move in the market or your career, Premium

Grab your flux capacitors, GPCR time travelers! Buckle up as we time-hop through this week's GPCR escapade!   Madelyn N Moore , Kelsey L Person , Abigail Alwin , Campbell Krusemark , Ezequiel Marron Fernandez de loss after a year, with no plateau INAUGURATION OF AELIS FARMA NEW LABORATORY at Institut Européen de

Terry Kenakin's insights on target residence time can reshape how you evaluate and advance lead compounds Terry's Corner - Unlock the Power of Target Residence Time in Your GPCR Drug Discovery Pipeline Gain Terry Kenakin’s latest insights delve into target residence time, revealing why kinetic persistence often

Using time-resolved cryo-electron microscopy (cryo-EM) and variability analysis to monitor the transitions Time-resolved cryo-EM of G-protein activation by a GPCR. Nature (2024).

When assays behave unpredictably, the wrong interpretation doesn’t just waste time; it costs viable compounds between stalled programs and breakthrough therapies often lies in a single insight delivered at the right time

is a guide to understanding why intracellular drug access changes everything: from target residence time receptor access alters diffusion, offset kinetics, and rebinding ✅ Real-world examples of how residence time—not Restricted Diffusion, Rebinding, and Residence Time: The Hidden Variables One of the most actionable Same Affinity, Different Outcomes: Why Residence Time Matters More Two ligands. Kenakin shows how this plays out in model systems and clinical data—and why residence time should be

Come attend this month's virtual café talk to see the awesome work of Dr. Stuart Maudsley on how an aging physiological context affects #GPCR signaling #drgpcr. Register here (FREE) https://www.ecosystem.drgpcr.com/dr-gpcr-virtual-cafe/ #gpcr #drgpcr #virtualcafe

September 2022 "Background and purpose: The interaction of arrestins with G-protein coupled receptors (GPCRs) desensitizes agonist-dependent receptor responses and often leads to receptor internalization. GPCRs that internalize without arrestin have been classified as "class A" GPCRs whereas "class B" GPCRs co-internalize with arrestin into endosomes. The interaction of arrestins with GPCRs requires both agonist activation and receptor phosphorylation. Here, we ask the question whether agonists with very slow off-rates can cause the formation of particularly stable receptor-arrestin complexes." Read more at the source #DrGPCR #GPCR #IndustryNews

January 2022 "Watch our CEO Tim Dyer on AlphaStreet. In his interview, Mr.

August 2022 A NanoBRET-Based H 3 R Conformational Biosensor to Study Real-Time H 3 Receptor Pharmacology characterized this H3R biosensor on intact cells by monitoring the effect of consecutive ligand injections in time

This belief that we don't have time to build better systems is a costly miscalculation. ,' only for the youngest to wisely respond, 'No, you just need to do one thing at a time .' This is the essence of de-risking GPCR programs through operational excellence. your drug discovery process from a series of disconnected efforts into a seamless, predictable, and de-risked Learn to translate your program’s internal operational precision into a compelling, de-risked narrative

is a guide to understanding why intracellular drug access changes everything—from target residence time The right information at the right time can mean the difference between a breakthrough and a dead end

Dimerization: Unveiling Its Role in Receptor Function and Signaling Sonja Peter , Brian Bender , Chris De signaling-competent receptors GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming

Over time, she developed a fascination with how molecules influence biology and how that chemistry could A postdoc in Santiago de Compostela introduced her to GPCRs, and from there, things escalated quickly

arrestin engagement, a biased NTSR1 modulator targets pain without the need for opioids, and a real-time conversation dives deep into the tools now transforming receptor biology—and how they’re being used to de-orphanize

Besides, it’s an eco-friendlier method, which always helps future-proof our probes!  C.; Henry De Villeneuve, C.; Moraillon, A.; Ozanam, F.; Gabouze, N.; Djebbar, S.

Member Profile Antony Boucard Professor Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav This was because, at that time, the neurexins, another family of adhesion molecules that also happened diversity among the aGPCR community, added to the fact that this will all take place for the first time There are a lot of firsts in this perspective: the first time in a LATAM country, the first organized AB: Favorite Taco: Taco de suadero (pronounced swa-day-ro), fatty, with meat caramelized in its own fat

Dimerization: Unveiling Its Role in Receptor Function and Signaling Sonja Peter , Brian Bender , Chris De signaling-competent receptors GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming

Boston, MA and Santiago de Compostela, Spain — [June 3rd, 2025]  — Dr. develops high-quality, fluorescently labeled ligands and innovative chemical biology tools to support real-time

A solid preclinical package, promising safety data, and a consistent in vivo proof-of-concept, it feels ✅ The sooner you understand what they’re optimizing for, the faster you can align your strategy to de-risk Because by the time they do, your timelines will stretch, your budgets will strain, and your confidence

experiments that enable operational clarity and avoid wasted effort ✅ The ability to reduce cycle times Your pipeline depends on early, well-informed decisions that move promising candidates forward while de-prioritizing are truly showing you can lead to costly missteps—wasted SAR iterations, false positives, and slower time-to-milestone questions that should shape your decision-making process: Are you measuring equilibrium, or could early-time-point

of GPCRs To study the dynamics of GPCRs, the imaging method must be spatially precise and have real-time They can be combined with other ligands and are very interesting in TR-FRET (Time-Resolved Förster Energy If the experiment is done on live cells , tracking real-time receptor internalization becomes possible Fluorescence Microscopy validation performed in the ONCOMET laboratory (Health Research Institute of Santiago de Cell-surface protein-protein interaction analysis with time-resolved FRET and snap-tag technologies:

GPCR consulting that cuts through the noise, designing assay cascades, setting go/no-go points, and de-risking

train in veterinary medicine, where he was introduced to physiology and pharmacology  for the first time Those courses didn’t feel like career-defining moments at the time — just requirements to pass. Emerging direction: Treatment sequencing + guided de-escalation.