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spatial availability or to remove them from in vivo sites, while maintaining the responsiveness of canonical Although less characterized, canonical CKRs have also been shown to not only directly regulate migration

Let’s dive into the Classified GPCR News from March 25th to March 31st, 2024 GPCR Activation and Signaling

Let’s dive into the Classified GPCR News from March 18th to 24th, 2024 GPCR Activation and Signaling Endpoints In The Phase 3 Pathfndr-2 Study In Acromegaly Patients GPCR Events, Meetings, and Webinars March

on Time-resolved cryo-EM of G-protein activation by a GPCR Remi Janicot, Alex Luebbers, Mikel Garcia-Marcos Let’s dive into the Classified GPCR News from March 11th to 17th, 2024 Adhesion GPCRs ADGRG1, an adhesion Therapeutics announces that is now part of Bristol Myers Squibb GPCR Events, Meetings, and Webinars March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition

Don't miss out, and mark your calendar! Dr. Let’s dive into the Classified GPCR News from March 4th to 10th, 2024 GPCR Activation and Signaling Glu1022.53 Deciphering the role of GPCRs in obesity pathology for drug development GPCR Events, Meetings, and Webinars March 13 - 15 | Biologics 2024 March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference

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 ➤

GPCR Symposia Mark your calendars! Next week, on March 15th, we are hosting a symposium on GPCR activation and signaling. Mark your calendar; we’re planning a workshop for May 2024 with Dr. Sam Hoare as our instructor. 13 - 15 | Biologics 2024 March 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference

Our guest is Mark Schmeizl!

Below is your Classified GPCR News at a glance for March 20th to 26th, 2023. Ends tomorrow - March 31st, 2023. (March 30, 2023) NEW Webinar - Antiverse: Engineering the Future of Drug Discovery (March 30, 2023) NEW Molecular Dynamics in Pharma (March 31, 2023) NEW FREE Workshop - Challenges in GPCR Drug Discovery (March 31, 2023) SLAS 2023 Building Biology in 3D Symposium.

Below is your Classified GPCR News at a glance for March 13th to 19th, 2023. Deadline extended to March 31st, 2023. (March 23, 2023) NEW 5th ERNEST GPCR ECI zoominar. (March 30, 2023) SLAS 2023 Building Biology in 3D Symposium.

GPCR Symposium event held on March 24th? Below is your Classified GPCR News at a glance for March 6th to 12th, 2023. Industry News Professor Dame Carol Robinson Received 2023 ASMS John.B.Fenn Award Exscientia Announces Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium.

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

GPCR Symposium event held on March 24th. that we can add it to the list of posters and increase the number of people who can ''stop by'' it on March Below is your Classified GPCR News at a glance for February 27th to March 5th, 2023. Deadline extended to March 31st, 2023. GPCR Events, Meetings, and Webinars ERNEST ECI zoominar. (March 9) GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium.

Mark Connor! Learn more about #GPCRs and life as an academic wearing different hats.

December 2021 OMass Therapeutics's founder, Carol Robinson, has been awarded the prestigious Louis-Jeantet Benjamin Franklin Medal in Chemistry from The Franklin Institute "Huge congratulations to our founder, Carol

March 2022 "Geneva, Switzerland, March 7, 2022 – Addex Therapeutics (SIX: ADXN, Nasdaq: ADXN), a clinical-stage and development, announced today that it will issue its full-year 2021 financial results on Thursday, March

June 2022 "June 15, 2022 06:30 AM EDT - In 2016, Abbie Celniker was promoted to partner at Third Rock Ventures as the firm raised just over $600 million for its fourth fund. Since then, Celniker has helped usher in an additional fund and headed a few startups as interim CEO. Coming on its 15th year, Third Rock Ventures announced its sixth fund today — and largest one by far — at a whopping $1.1 billion. Adding it all up, Third Rock has raised $3.8 billion since its inception. That money has gone to some 60 biotechs, much of it as early funding." Read more at the source #DrGPCR #GPCR #IndustryNews

Kathleen M Caron and her team studied the GPER/GPR30 complex with β1-adrenergic receptor and AKAP5 in GPCR Partnered Events March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit Exciting news! We're partnering again with the 3rd GPCRs - Targeted Drug Discovery Summit in Boston on March 5-7, 2024 | SLAS2024 International Conference and Exhibition February 11 - 14, 2024 | 2024 BPS Annual Meeting March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition

You can find more details about the speakers on the Live Talks page, and make sure to mark your calendar Kathleen Caron, as our video guest, subscribe now! | 23rd Annual PEP Talk February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition NEW March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition and Molecular Gating Conference NEW

Find speaker details on the Live Talks page and mark your calendar HERE. Kathleen Caron. Check out the weekly Classified GPCR News from October 23rd to 29th, 2023. ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition

Don't forget to mark your calendars for July 21st, as the upcoming Dr. Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March 24 - 29, 2024) GPCR Jobs NEW Postdoctoral Fellow, Caron Lab NEW Clinical Trial Associate Research Scientist

, 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March Senior Scientist- Membrane Technologies NEW Computational Protein Design (GPCR) Postdoctoral Fellow, Caron

GPCR Symposia Our upcoming symposium on March 15th is about GPCR activation and signaling. GPCR Partnered Events March 5 - 7, 2024 | 3rd GPCRs - Targeted Drug Discovery Summit Join us at the 3rd GPCRs Summit in Boston on March 5-7, 2024. spatially selective GPCR signaling GRK5 promoted renal fibrosis via HDAC5/Smad3 signaling pathway Non-canonical 13 - 15 | 9th German Pharm-Tox Summit March 23 - 24, 2024 | Ligand Recognition and Molecular Gating

Targeting GRK2 and GRK5 for treating chronic degenerative diseases: Advances and future perspectives Non-canonical GPCR early career investigator (ECI) Zoominar Survey 2nd ERNEST Training School – February 20th to March GEM2023 (14-17 March 2023). 8th and final ERNEST Meeting May 3-7, 2023 in Crete.

Find speaker details on the Live Talks page and mark your calendar HERE. Kathleen Caron. Check out the weekly Classified GPCR News from October 30 to November 4, 2023. ASCEPT Annual Scientific Meeting February 3 - 7, 2024 | SLAS2024 International Conference and Exhibition March 23 - 24, 2024 | Ligand Recognition and Molecular Gating Seminar March 24 - 29, 2024 | Ligand Recognition

Recently, Suchismita Roy et al. have explored how growth factors can modulate canonical G protein signaling research question addressed in this study was: How do growth factors, specifically through RTKs, modulate canonical cleft and P loop uncouple G proteins from GPCRs, leading to segregation of RTK-to-Gαi pathways from canonical For instance, the sequestration of G proteins from canonical GPCR-dependent pathways by growth factor Growth factor-dependent phosphorylation of Gαi shapes canonical signaling by G protein-coupled receptors

Mark your calendars for the upcoming Dr. , 2023) Structure, Mechanism, and Drug Interactions of GPCRs, Ion Channels, and Transport Proteins (March Surgery Senior Scientist- Membrane Technologies Computational Protein Design (GPCR) Postdoctoral Fellow, Caron

Small-molecule targeting of GPCR-independent non-canonical G protein signaling inhibits cancer progression Deadline extended to March 31st, 2023. (February 20 - March 3, 2023). (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 Building Biology in 3D Symposium.

February 16 - 21, 2025 | Harnessing the Power of Advanced Multimodal Approaches to GPCR Drug Discovery March 12 - 14, 2025 | NextGen Biomed 2025 March 25 - 28, 2025 | 10th German Pharm-Tox Summit April 1 - 5, Activation and Signaling Pathophysiological significance and modulation of the transient receptor potential canonical

Non-canonical Golgi-compartmentalized Gβγ signaling: mechanisms, functions, and therapeutic targets. Deadline extended to March 31st, 2023 GPCR Events, Meetings, and Webinars 2nd GPCR-Targeted Drug Discovery SLAS2023 International Conference and Exhibition (February 25 - March 1, 2023). 2nd ERNEST Training School (February 20 - March 3, 2023). (March 2, 2023) GEM2023. (March 14-17, 2023). SLAS 2023 B uilding Biology in 3D Symposium.