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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

GPCR University Get ready for our next Dr. GPCR University hands-on workshop with Dr.  Hoare and Dr. GPCR Complementary one-year Dr. Dr. GPCR Symposia With a premium membership, you can watch on-demand the Dr. Dr. Let’s dive into the Classified GPCR News from March 25th to March 31st, 2024 GPCR Activation and Signaling

Additionally, we are having a Panel Discussion on Publishing in Academia with Drs. Dr. GPCR University Save the date for our upcoming workshop starting May 9th, 2024, featuring Dr. Gain invaluable skills in data analysis under Dr. Hoare's expert guidance. Dr. Terry Kenakin's "Applying Pharmacology to Drug Discovery" course at Dr. Dr.

work on Direct interrogation of context-dependent GPCR activity with a universal biosensor platform Dr Dr. GPCR University Save the date for our upcoming workshop, starting May 9th, 2024, featuring Dr.  Under Dr. Hoare's expert guidance, you will gain invaluable skills in data analysis. Dr. Terry Kenakin's "Applying Pharmacology to Drug Discovery" course at Dr. Dr.

This week's highlight includes congrats to: Drs.  Dr. GPCR Symposia With a premium membership, you can watch on-demand the Dr. Dr. Let’s dive into the Classified GPCR News from March 18th to 24th, 2024 GPCR Activation and Signaling Behavior Director of Laboratory Operations - Single-molecule Imaging Center Scientific Assistant Join Dr

This week's highlight includes congrats to: Christina Katharina Kuhn, Drs. Howard Rockman, and Dr.  We are delighted to confirm the participation of esteemed speakers such as Drs.  Dr. GPCR University Great News! The Dr. Dr.

Hello Readers👋, We're excited to have you in the Dr. GPCR Ecosystem. For Dr. GPCR News, subscribe to our monthly newsletter. This month on the Dr. GPCR News video edition, we chatted with Dr. Oliver Hartley. Ends tomorrow - March 31st, 2023. Explore Dr. GPCR Ecosystem

βarrestin-independent GPCR endocytosis Valeria Robleto , Ya Zhuo , Joseph Crecelius , Sara Benzow , Adriano Marchese Cannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons Rafael reveals insights into mechanisms of GPCR signaling Larissa Silva , Anuradha Wijesekara , Matthew Eddy At Dr Embrace the excitement of supporting us and unlocking incredible perks such as: Dr. Direct line to the Dr.

To get the latest, Dr. GPCR News, don't forget to sign up for our monthly newsletter. Are you ready for our first Dr. GPCR Symposium event held on March 24th? Below is your Classified GPCR News at a glance for March 6th to 12th, 2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium. Explore Dr. GPCR Ecosystem

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For more great content, subscribe to our Dr. GPCR News monthly newsletter. Also, please mark your calendar for the next Dr. or present a poster, email us at Hello@DrGPCR.com Below is your Classified GPCR News at a glance for March Informatics Head or Team Lead (depending on experience) with Structural Bioinformatics Expertise Explore Dr

Drug discovery does not move in fixed conclusions. As datasets expand and systems are tested under new conditions, interpretations often require adjustment. What initially appears mechanistically clear can become more nuanced when additional experiments are layered in. Terry’s Pharmacology Corner is built around that reality. It is designed as a continuous learning environment — supporting scientific reasoning as programs mature, rather than treating pharmacology as a one-time lesson. The analysis below emerged from a recent live Ask Me Anything (AMA) session, where members brought forward active questions from their GPCR discovery efforts. The AMA format enables careful examination of evolving data — from Schild slope interpretation to probe dependence and kinetic validation — in real time. Through structured lectures, monthly live AMAs, and full replay access, the Corner provides ongoing refinement of pharmacological judgment across the lifespan of a program. The next live AMA will take place: Thursday, February 26th at 12:00 PM EST You are invited to submit questions in advance to: terry@drgpcr.org Distinguishing Orthosteric vs Allosteric Mechanisms in GPCR Drug Discovery Programs Pharmacologists know the pressure of distinguishing between orthosteric and allosteric drug mechanisms—especially when structural data is unavailable. Functional assays can suggest clarity while quietly masking complexity, creating the illusion of competitive antagonism or obscuring subtle allosteric behavior. Misinterpretation does more than delay progress. It can redirect chemistry strategy, distort translational assumptions, and conceal liabilities that emerge only in vivo or in the clinic. What if a seemingly “clean” antagonist profile reflects silent allosteric modulation? What if probe dependence is quietly signaling selective safety implications? Each experimental decision — system sensitivity, assay configuration, kinetic design — carries strategic consequences. In this session, we explored: Strategic frameworks for early discrimination of orthosteric vs allosteric effects Conceptual tools for interpreting Schild plot deviations and probe dependence Operational practices that strengthen GPCR discovery pipelines Operationalizing Allosteric Signatures Early workflows often rely on rapid “one-way” experiments — screens that may reveal allosteric behavior but cannot definitively exclude it. A substantial rightward shift in a dose–response curve is frequently interpreted as competitive antagonism. However, negative allosteric modulators (NAMs) with modest cooperativity can mimic orthosteric competition across wide concentration ranges. The defining distinction is saturation: Saturation defines the allosteric boundary  — additional modulator produces no further shift. Orthosteric antagonists remain theoretically unlimited  — competition continues as concentration increases. Recognizing this difference early prevents mechanistic misclassification. Interpreting Schild Plots — Curves and Slopes Schild analysis remains foundational, but interpretation requires discipline. When a system approaches full allosteric occupancy, the Schild plot curves and the slope falls below unity — signaling that competitive assumptions no longer apply. Key diagnostic considerations: Curved Schild plots suggest occupancy-limited modulation Linear plots with slope ≠ 1 demand investigation  — equilibration time, receptor heterogeneity, or system-level factors must be assessed before mechanistic conclusions are drawn A slope is not merely a fitted parameter. It is a diagnostic signal. Probe Dependence — A Distinctive Allosteric Readout Allosteric systems exhibit probe dependence: the same modulator can shift one agonist thirty-fold and another six-fold. This variability is not noise — it is mechanistic information. Probe dependence reveals hidden selectivity and efficacy shifts It becomes critical in both screening strategy and therapeutic positioning As ligand diversity expands — including peptide agonists and biased ligands — ignoring probe dependence risks overlooking clinically meaningful distinctions. Assay Sensitivity and System Configuration Receptor expression level is a strategic variable. High-expression systems maximize detection sensitivity and can reveal subtle efficacies. Low-expression systems expose whether observed potency reflects intrinsic efficacy or simple binding strength. This “tissue volume control” becomes essential when: Distinguishing affinity-dominant from efficacy-dominant agonists Detecting silent partial agonism Extracting operational model parameters with translational relevance System configuration shapes interpretation. Decoding Kinetics — The Allosteric Differentiator Kinetic experiments provide definitive mechanistic evidence. Only allosteric modulators alter the onset or offset of agonist responses. Demonstrating changes in association or dissociation rates moves analysis beyond functional shifts toward mechanistic proof. Allosterics modify agonist kinetics Orthosteric competitors do not For publication-grade validation and regulatory confidence, kinetic evidence becomes indispensable. Strategic Use of Repurposing and Data Controls Drug repurposing offers reduced uncertainty and extensive prior data. Yet rare adverse effects may only emerge after large-scale exposure, and selectivity must still be demonstrated rigorously. Meanwhile, controls remain non-negotiable. GPCR systems are sensitive and context-dependent. Pathway bias, tissue sensitivity, and system artifacts can distort interpretation if not carefully managed. Robust controls distinguish mechanism from artifact Multipathway analysis reduces false confidence Neglecting these elements invites downstream surprises. Integrating Chemistry and Kinetics Early Biological activity alone does not define a viable series. Chemical tractability, early safety screens (e.g., hERG), ADME properties, and residence time often determine long-term success. Potency can attract attention, but residence time and target engagement kinetics frequently better predict in vivo performance. Strategic discipline means: Screening liabilities early Integrating chemistry insights immediately Avoiding advancement of scaffolds likely to collapse later “Fail early” is not pessimism. It is resource stewardship. Best Habits for Data Quality and Reproducibility Detection assays identify activity; they do not validate therapeutic viability. Repetition without purpose consumes time. Statistical rigor prevents wishful interpretation. Quantitative follow-up studies separate true signal from noise. Advance promising hits into mechanistic evaluation quickly Use statistics to arbitrate interpretation Design assays deliberately Interpretive discipline is the foundation of reproducible pharmacology. Why Terry’s Pharmacology Corner Mechanistic understanding evolves. What appears settled under one experimental condition may require refinement under another. Terry’s Pharmacology Corner provides a structured environment for that evolution: Weekly advanced pharmacology lectures Monthly live AMAs for real-time scientific discussion A continually expanding on-demand archive Sustained exposure to disciplined mechanistic reasoning The value lies not in a single explanation, but in maintaining interpretive rigor as programs mature. Forty years of pharmacological expertise — organized into a year-round learning framework for serious GPCR scientists. Explore the full library ➤

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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.

Hello Sweet GPCR Enthusiasts, This week at Dr. GPCR: a new podcast episode with Dr. Ben Clements, a tour of our official Dr. Scroll down for the science, the strategy, and the sweet stuff 🍬 Dr. The official Dr. GPCR Store is live! Best wishes, The Dr. GPCR Team

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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

Secure Your Access Now ➤ 🗣️ “Thank you for bringing this (Principles of Pharmacology I) course with Dr I wish Dr. best for the sake of promoting more educational opportunities that are sorely needed in the field” — Dr GPCR University Learner Dr. GPCR Podcast - Surviving Discovery’s Gauntlet Dr. The Dr. GPCR Team Read Full Edition ➤

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

In this Terry’s Corner lesson, Dr. Join before year-end to secure both. 👉   Join Terry's Corner Before Dec 31st, 2025 🎧 Dr. Hudson 🎧 Catch up on Part 2 with Dr. GPCR Year in Review: Carrying Better Experiments Into 2026 As 2025 closes, the Dr. Beyond access, Premium sustains the nonprofit mission behind Dr.

. -            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.

For Dr. In this episode of the Dr. ” — Dr. Maria Majellaro Maria’s career didn’t start with a desire to launch a company. Celtarys Research, now partnering with Dr. ____________ Keyword Cloud:   GPCR drug discovery , GPCR research community , medicinal chemistry , Dr

Dr. GPCR Podcast: Chemical Probes for GPCR Imaging with Dr. In this episode, Dr. I will keep Dr. GPCR and the offered resources in my work sphere." Donate : https://www.ecosystem.drgpcr.com/donate Dr.

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