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September 2022 "Morphine, the most widely used analgesic, relieves severe pain by activating the μ-opioid receptor (MOR), whereas naloxone, with only slight structural changes compared to morphine, exhibits inhibitory effect, and is used to treat opioid abuse. The mechanism by which the MOR distinguishes between the two is unclear. Molecular dynamics (MD) simulations on a 1-μs time scale and metadynamics-enhanced conformational sampling are used here to determine the different interactions of these two ligands with MOR: morphine adjusted its pose by continuously flipping deeper into the pocket, whereas naloxone failed to penetrate deeper because its allyl group conflicts with several residues of MOR. The endogenous peptide ligand endomorphin-1 (EM-1) underwent almost no significant conformational changes during the MD simulations. To validate these processes, we employed GIRK4S143T, a MOR-activated Gβγ-protein effector, in combination with mutagenesis and electrophysiological recordings. We verified the role of some key residues in the dynamic recognition of naloxone and morphine and identified the key residue I322, which leads to differential recognition of morphine and naloxone while assisting EM-1 in activating MOR. Reducing the side chain size of I322 (MORI322A) transformed naloxone from an inhibitor directly into an agonist of MOR, and I322A also significantly attenuated the potency of MOR on EM-1, confirming that binding deep in the pocket is critical for the agonistic effect of MOR. This finding reveals a dynamic mechanism for the response of MOR to different ligands and provides a basis for the discovery of new ligands for MOR at the atomic level." Read more at the source #DrGPCR #GPCR #IndustryNews

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

For Dr. In this episode of the Dr. ” — Dr. Maria Majellaro Maria’s career didn’t start with a desire to launch a company. A postdoc in Santiago de Compostela introduced her to GPCRs, and from there, things escalated quickly Celtarys Research, now partnering with Dr.

This week at Dr. Dr. Led by Dr. Tom Sakmar and Dr. conversation dives deep into the tools now transforming receptor biology—and how they’re being used to de-orphanize

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Explore 10 on-demand lessons by Dr. GPCR consulting that cuts through the noise, designing assay cascades, setting go/no-go points, and de-risking Visit Yamina’s Corner Now CELT-335 - Celtarys Validates New Assay for CB1/CB2 Screening Dr. Stay curious,   The Dr. GPCR Team Join Our Newsletter!

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Dimerization: Unveiling Its Role in Receptor Function and Signaling Sonja Peter , Brian Bender , Chris De Thank you to all participants in Dr. Terry Kenakin's educational initiative this fall! signaling-competent receptors GPCRs in Neuroscience Astrocyte Gi-GPCR signaling corrects compulsive-like grooming

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In Episode 168 of the Dr. GPCR Podcast, Dr. And that mindset is precisely what makes their new partnership with Dr. GPCR so powerful. ” — Dr. That’s the mission. ” — Dr. Maria Majellaro Now, as official partners of the Dr. Keyword Cloud:   GPCR data platform , fluorescent ligands , assay development , GPCR research community , Dr

Dr. Maria Majellaro’s story, shared in Episode 168 of the Dr. ” — Dr. Maria Majellaro Maria didn’t always know she’d end up in a startup. ” — Dr. With the new  Dr. . 👉 Explore Celtarys’ tools and partnership with Dr.

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, we’re spotlighting Celtarys Research, our newest partner, featured in a blog and podcast with CSO Dr After 40+ years and 250 publications, Dr. Dr. Explore Terry's Corner From Chemistry Lab to GPCR Partner – New Podcast with Celtarys Dr. Stay curious, The Dr. GPCR Team

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GPCR Podcast: Leadership, Impact, and GPCR Signaling with Dr. Dr. Yamina’s open letter reflects on how Dr. I wish Dr. No matter where you are in your GPCR journey, Dr.

The Corner comes will live monthly AMA sessions with Dr. Kenakin. GPCR Updates Learn Pharmacology That Drives Discovery  – From Dr. Explore Dr. This blog post breaks down Dr. Stay curious,   The Dr. GPCR Team

GPCR Colleagues & Curiosity-Driven Minds, We’re starting with exciting Dr. sharpen your skills with our new on-demand course, Techniques for Effective Lead Optimization with Dr Dr. Catch up on past Dr. Stay curious, The Dr. GPCR Team

. -            Dr. Wendy Young’s talk, during session 3 on day 2, was also incredible. . -            Dr. Wednesday was a key day for Maria, as she got to participate in a panel discussion alongside Dr. Shoichet, Dr. Luc Van Hijfte and Dr. Wendy Young. Amanda Dombrowski from Abbvie, Dr. Charles Yeung from Merck and Dr.

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This week's highlights: Dr. Norton Cheng and Dr. Dr. Thomas P. Our confirmed speakers are Dr. Xavier Leroy, Dr. Brian Arey, and Dr. J. Silvio Gutkind. Subscribe to Dr. GPCR Newsletter for more insights!

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Hello GPCR Innovators ,   We’re preparing to launch Terry’s Corner, a new knowledge hub shaped by Dr. Plus, Celtarys explores ligand selection for better assays, and co-founder Dr. pain relief in preclinical models Dr.GPCR Updates Terry’s Corner  – Build Better GPCR Screens with Dr Screening Strategy Leadership in Ligand Design  – The Celtarys Origin Story   In  this founder interview , Dr Best,   The Dr. GPCR Team