Insights That Move the GPCR Field Forward

Discovery programs rarely fail because a molecule “did nothing.” They fail because a molecule behaved exactly as the underlying system allowed—amplified, buffered, redirected, or reshaped by layers of receptor biology that weren’t accounted for. The October 30th AMA with Dr. Kenakin highlighted a fundamental truth: GPCR systems do not offer stable, proportional input–output relationships. Receptor density, constitutive activity, coupling efficiency, local signaling archit

Drug discovery often assumes receptor inhibition follows simple rules—agonist binds, antagonist blocks, and data fit neatly into predictable curves. Yet, any pharmacologist who’s pushed beyond textbook theory knows: biology rarely plays fair. Schild analysis remains one of the few conceptual anchors that can tell us when “simple” truly is simple—and when deeper receptor dynamics are at play.

Drug discovery pipelines often stall not because the target is wrong—but because the chemical matter interacting with that target lacks the right properties to produce meaningful pharmacology. We obsess over target validation, signaling pathways, expression patterns, and disease relevance. Yet, far less time is spent scrutinizing the structural logic and origin of the molecules we screen in the first place.

Nine out of ten GPCR programs stall not because the target was wrong, but because teams waited too long to test the right thing. Terry Kenakin has seen this story play out for 40 years — and he’s rewriting the ending.

Early signals can mislead. This week’s Dr. GPCR Weekly shows how to call Mechanism of Action with model-first rigor—distinguishing orthosteric vs. allosteric, designing assays that reveal mechanism, and unlocking SAR. Plus: Novo’s \$550M obesity/diabetes push, Rhythm’s sNDA, key events, and confocal imaging that respects function. Upgrade to Premium for the full digest.

October 2022 Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin...