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In Terry Kenakin’s latest lesson, you’ll uncover why efficacy is the unsung hero of drug discovery and You'll learn why some agonists succeed in sensitive tissues but fail elsewhere—and how this knowledge can dramatically shift your screening strategy. If you’re stuck trying to figure out why your lead compound looks promising in vitro but flops in vivo , you need this lesson.

Welcome to Terry’s Corner , where foundational pharmacology is demystified by someone who’s spent over 40 years You’ll uncover: Why pharmacology is the glue between chemistry and biology How to interpret drug behavior Whether you're heading into your first assay or trying to make sense of inconsistent data, Terry gives you the tools and mindset to understand what's really  happening. Don’t just look at the data—learn how to read the story it’s telling. 👉 Start your journey with Terry

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We've got an early holiday treat for you: The University CheatSheet ! We are bursting with pride in sharing it with you, and we sincerely want to thank you for your support over the years. This is your last call before the curtain drops: Classified GPCR News is going VIP-only next year! Get your 5-day free trial TODAY!

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Welcome back to your weekly GPCR quest! Thank you to all participants in Dr. Terry Kenakin's educational initiative this fall! Your dedication has greatly enriched the learning experience. and Financing Deal of the Year at the Citeline Japan Awards 2024 GPCR therapies: Eight promising biotechs Get your 5-day free trial TODAY!

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G protein-coupled receptors (GPCRs) are major drug targets, yet their complex and dynamic structures Docking 490 million molecules against the σ2 receptor's AF2 model yielded a 54% hit rate, comparable

therapeutic intervention for metabolic diseases such as liver disease, obesity and diabetes (Wold and Zhou

However, at that time the structural conformation of the transmembrane (TM) region was not yet known. Fortunately, the scientific community has become increasingly interested in studying these proteins and this year Ping, Y.-Q., et al., Structural basis for the tethered peptide activation of adhesion GPCRs. Qian, Y., Ma, Z., Liu, C., Li, X., Zhu, X., Wang, N., Xu, Z., Xia, R., Liang, J., Duan, Y., Yin, H., Xiong, Y., Zhang, A., Guo, C., Chen, Z., Huang, Z., & He, Y. (2022).

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

YM-254890 (YM) can inhibit signaling by both GPCR-activated wild type αq and GPCR-independent αqQ209L Although YM inhibits wild type αq by binding to αq-GDP and preventing GDP/GTP exchange, the mechanism of YM inhibition of cellular αqQ209L remains to be fully understood. Here, we show that YM promotes a subcellular redistribution of αqQ209L from the plasma membrane (PM) Treatment of cells with YM failed to inhibit signaling by these PM-restricted αqQ209L.

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September 2022 Opposite Effects of Src Family Kinases on YAP and ERK Activation in Pancreatic Cancer Crucially, SFKs promoted YAP nuclear localization and phosphorylation at Tyr357, as shown by using the SFK inhibitors dasatinib, saracatinib, the preferential YES1 inhibitor CH6953755, short interfering RNA (siRNA)-mediated knockdown of YES1 and transfection of epitogue-tagged YAP mutants in PANC-1 and , our results also demonstrate that exposure to SFK inhibitors, including dasatinib or knockdown of YES

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allosteric modulation-based drug discovery and development, announced today that it will issue its full-year

company pioneering allosteric modulation-based drug discovery and development, today reported its half-year

July 2022 "G.CLIPS biotech is 2 years old today🎂.

July 2022 "Today we are celebrating ten years of Exscientia! of a global company with locations in the UK, U.S., Austria, and Japan which IPO’d in October last year We’re excited about delivering the next ten years of Exscientia and advancing AI to design better drugs

Coming on its 15th year, Third Rock Ventures announced its sixth fund today — and largest one by far

October 2022 "Systolic heart failure (HF) is a chronic clinical syndrome characterized by the reduction in cardiac function and still remains the disease with the highest mortality worldwide. Despite considerable advances in pharmacological treatment, HF represents a severe clinical and social burden. Chronic human HF is characterized by several important neurohormonal perturbations, emanating from both the autonomic nervous system and the adrenal glands. Circulating catecholamines (norepinephrine and epinephrine) and aldosterone elevations are among the salient alterations that confer significant hormonal burden on the already compromised function of the failing heart. This is why sympatholytic treatments (such as β-blockers) and renin-angiotensin system inhibitors or mineralocorticoid receptor antagonists, which block the effects of angiotensin II (AngII) and aldosterone on the failing heart, are part of the mainstay HF pharmacotherapy presently. The adrenal gland plays an important role in the modulation of cardiac neurohormonal stress because it is the source of almost all aldosterone, of all epinephrine, and of a significant amount of norepinephrine reaching the failing myocardium from the blood circulation. Synthesis and release of these hormones in the adrenals is tightly regulated by adrenal G protein-coupled receptors (GPCRs), such as adrenergic receptors and AngII receptors. In this review, we discuss important aspects of adrenal GPCR signaling and regulation, as they pertain to modulation of cardiac function in the context of chronic HF, by focusing on the 2 best studied adrenal GPCR types in that context, adrenergic receptors and AngII receptors (AT 1 Rs). Particular emphasis is given to findings from the past decade and a half that highlight the emerging roles of the GPCR-kinases and the β-arrestins in the adrenals, 2 protein families that regulate the signaling and functioning of GPCRs in all tissues, including the myocardium and the adrenal gland." Read more at the source #DrGPCR #GPCR #IndustryNews

If you want to showcase your research, you can submit a poster presentation to our community, take advantage you could complete this survey. Your opinion is valuable to us. Dr. AlphaFold2 predicted water-soluble QTY variants and uncovering the natural mutations of L->Q, I->T, F->Y and Q->L, T->I and Y->F Industry News Sosei Heptares Doses First Subject in Phase 1 Trial with HTL0033744

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

detection, receptor activation initiates conformational changes, exposing an intracellular cavity (Kang, Y. While some receptors selectively activate specific G protein families, others are more versatile, yielding and overall conformational states (Kang, Y. et al. 2015). β-arrestins, paving the way for capturing challenging protein complexes (Böttke, T., et al. 2020, Aydin, Y. -Y. et al 2018).

Gurevich, et al. 2018; Y. A. Berchiche et al. 2011). The ability to rapidly recycle, which was shown by a chemokine washout BRET assay (Y. likely to be mediated by changes in the cell motility machinery with receptor-specific switches not yet CCR2 inhibition leads to inhibition of scavenging and elevated plasma levels of CCL2 (Y.

You can consult the article at the following link: https://www.ecosystem.drgpcr.com/structural-and-molecular-insights-into-gpcr-function Goswami, Y. Zhang, A.J.M. Molina, T.C. Südhof, and R.C. Malenka. 2013. Mozhayeva, Y. Sara, T.C. Südhof, and ¨ E.T. Kavalali. 2001.

If you’ve read our previous post, you probably know what CELT-335 is and its high affinity for the cannabinoid If you want to check out the Materials and Methods section as well as the application note, here is the If you are interested in our ligands or technology, feel free to contact me anytime. References 1. isolated from Cannabis   sativa , Scientifi c Reports (2020) 10(1):20405. doi: 10.1038/s41598-020-77175-y

tail-suspension and forced-swim tests, and comparable learning and memory abilities in the Morris water maze, Y

Impact of GRK3 on YAP1 and its targets was determined."