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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

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

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).

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

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

notable differences in respect to neural network architecture, complexity, data requirements, training time DL models generally require more computational resources (such as powerful GPUs) and longer training times De novo drug design: AI algorithms can generate new molecules with desired properties, such as binding chemical space, limiting their ability to identify truly novel chemotypes”(Thomas, Smith, O’Boyle, de

This week's highlight includes congrats to Omolade Otun, Chris de Graaf, Cherine Bechara, et al. for Understanding real-time kinetics to predict activity and in vivo target coverage.

membrane-embedded opsin indicated that phospholipid headgroups traverse a dynamically revealed hydrophilic groove cholesterol inhibits phospholipid scrambling by occupying the TM6/7 interface and stabilizing the closed groove

As well, fluorescent ligands were effective at monitoring real-time A2BAR receptor labeling using live-imaging This proof-of-concept study suggests the use of fluorescent ligands for GPCR characterization through

Domain Therapeutics was nominated for the Trophée de l'Innovation Technologique (Technological Innovation

Therefore, matching a ligand to an orphan GPCRs, the process of de-orphanizing, is of great importance

dynamics simulations of opsin in a lipid membrane reveal conformational transitions that expose a polar groove This groove enables transbilayer lipid movement, conceptualized as the swiping of a credit card (lipid

Michel Bouvier received the title of Doctor Honoris Causa from the Université de Montpellier Domain Therapeutics

Adhesion GPCRs Optimized genetic code expansion technology for time-dependent induction of adhesion GPCR-ligand ended 31 December 2022 Addex Raises $5.0 Million in Equity Financing Testing the limits of SMILES-based de

GPCR drugmaker Septerna amasses $288M in IPO Surrounded by AI bio giants, tiny startup Nabla Bio makes de

Our work provides proof of concept for the modulation of isoform- and ligand specific aGPCR functions

This week's highlight includes congrats to: Tessa de Vries, Graham Ladds, Antoinette MaassenVanDenBrink

November 2021 "Nov. 15, 2021 LONDON – There’s not yet proof of the pudding, but Omass Therapeutics Ltd

Topics cover new cellular assays, real-time kinetics, and unique GPCR behaviors. GPR37-mTOR-S6K1 Signaling GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming

Venture-like’ capital allocation approach to focus pipeline development through to Phase 1b/2a clinical proof

The researchers conducted a comparative analysis with previous studies, notably the work by Groot-Kormelink