Mechanism vs. Assumption: A Model-First Path to Getting GPCR MoA Right
- Dr. GPCR News
- Sep 11
- 4 min read
Hi GPCR Community,
If you work on GPCR discovery, you already know: early signals can mislead, and timing your next decision is career-critical.
This week, we focus on how to convert ambiguous data into confident, defensible Mechanism of Action calls—before resources drift. That’s precisely what Terry’s Corner delivers every week: practical tools from Dr. Terry Kenakin to elevate your science and sharpen your decisions.
Breakthroughs this week: 5-MeO-DMT: the "God Molecule"; Novo Nordisk looks to next generation of obesity, diabetes drugs with $550M Replicate research deal; Rhythm Pharmaceuticals Announces FDA Acceptance of sNDA for Setmelanotide in Acquired Hypothalamic Obesity.
🔍 This Week in Dr. GPCR Premium: Sneak Peek
A fast, editorial preview—enough to guide your attention, not replace your due diligence.
Industry insights: Biopharma returns to MC4R; Recursion completes Exscientia acquisition, signaling a fresh AI–GPCR chapter; OMass–Genentech deal in IBD.
Upcoming events: “Drug Discovery at Superluminal Speeds”; and Discovery on Target 2025—GPCR track you’ll want on the calendar.
Career opportunities: Research Assistant; Postdoctoral Associate; Senior Scientist, Data Science—curated roles aligned to GPCR discovery and translational pharmacology.
Must-read publications: β-arrestin2-biased allosteric modulator for pain beyond opioids & GPR3 regulated by a negative allosteric modulator
Terry's Corner – Determine GPCR MoA Early (and Right)
Early discovery often serves you overlapping curves and noisy baselines; different mechanisms can masquerade as the same “effect.”
This week’s Terry’s Corner lesson shows how to replace inference with models that disentangle mechanism—so your next go/no-go, dose range, and assay design are anchored in prediction, not intuition.
You’ll apply a model-first workflow to classify orthosteric vs. allosteric behavior, stress-test assumptions through fit→predict→test loops, and improve SAR by separating affinity from efficacy.
What you’ll gain—immediately relevant to your pipeline:
Stop costly misreads: Distinguish orthosteric vs. allosteric effects by extending predictions, not eyeballing plots—so you don’t advance a “hit” that collapses in validation.
Engineer assays on purpose: Set ranges, controls, and system sensitivity to surface mechanism—before you lock in a screen that hides the signal you need.
Unlock real SAR: Deconvolute potency into affinity vs. efficacy to make medicinal chemistry cycles more informative—and faster.
Premium Members get a 50%+ discount when they join Terry’s Corner.
🚨 First-ever Live AMA with Dr. Kenakin is happening September 18th, 12- 1 pm EST —exclusively inside Terry’s Corner. Bring the curve you’re debating. Ask. Challenge. Get an answer you can defend.
Celtarys Research – Confocal Imaging That Preserves GPCR Function
Confocal imaging can clarify GPCR localization, trafficking, and dynamics—if your probes preserve function, minimize phototoxicity, and work in both live and fixed contexts.
This applied article walks through ligand-directed labeling, SNAP/Halo tags, and fluorescent ligands tied to pharmacophores—plus how to choose probes for your biological context and temporal resolution. Expect practical guidance on TR-FRET compatibility, photobleaching resistance, and 3D stack acquisition for tissue-like environments.
Why it matters now:
Cleaner signal: Selective excitation + low background reduces false positives in trafficking and clustering studies.
Physiological relevance: Fluorescent ligands can retain receptor integrity—critical when signaling readouts drive decisions.
Assay flexibility: Combine self-labeling tags with quantitative readouts (e.g., TR-FRET) to expand mechanism insight.
Discovery on Target 2025 – GPCR Speaker Spotlight
DOT 2025 (Sept 22–25, Boston) is set to be a high-signal GPCR forum—bridging biased signaling, allostery, and structure-guided design across oncology, metabolic, CNS, and fibrosis programs. This week, get to know Dr. Aaron McGrath from Takeda. He joins Dr. Yamina Berchiche to discuss:
🔹 Why PAR1 and PAR2 are such unique GPCRs
🔹 What structural biology is teaching us about shallow orthosteric pockets and druggability
🔹 The role of cryo-EM in capturing fully activated GPCR complexes
📅 Catch Aaron’s full talk at Discovery on Target, Sept 24–25 in Boston.
🎥 Plus, join us at the GPCR Track, GPCR Happy Hour, and more!
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It’s built for scientists and leaders who want the signal, not the scroll: frameworks that clarify mechanism, context that sharpens strategy, and a community that accelerates collaboration.
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🔹 Why now?
GPCR innovation is accelerating. Those acting on the right signals today will shape tomorrow’s breakthroughs—and avoid delays others won’t see coming.
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Ready to turn ambiguous signals into confident, defensible decisions—and join a community designed to move science forward?
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