The first GPCR Pharmacology AMA of 2026 takes place February 26 at 1 PM EST. Join Terry’s Corner to discuss receptor theory, biased signaling, and mechanistic interpretation in drug discovery.

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.

In early-stage drug discovery, one miscalculated liability can bring an otherwise promising scaffold to a complete halt. Rushing past early safety signals, especially those emerging from cytotoxicity or off-target activities, risks catastrophic consequences for both patient safety and project resources.

Binding affinity appears straightforward: add ligand, measure signal, fit a curve. Yet discovery teams routinely lose time and misallocate resources because the underlying biology behaves nothing like the idealized systems we learned in textbooks. GPCRs couple, decouple, isomerize, deplete tracers, and shift apparent affinity depending on stoichiometry and time. The result is a recurring pattern across programs—clean data that is not actually telling the truth. Orthosteric bi

Binding affinity appears straightforward: add ligand, measure signal, fit a curve. Yet discovery teams routinely lose time and misallocate resources because the underlying biology behaves nothing like the idealized systems we learned in textbooks. GPCRs couple, decouple, isomerize, deplete tracers, and shift apparent affinity depending on stoichiometry and time. The result is a recurring pattern across programs—clean data that is not actually telling the truth. Orthosteric bi

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.

This session unpacks how persistent binding can either accelerate your program—or quietly kill it. That’s the power (and the peril) of irreversible drugs. These aren’t just “stronger binders.” They’re kinetic game-changers—compounds that rewrite the relationship between ligand, receptor, and physiologic outcome. Understanding how persistent binding affects receptor turnover, tissue penetration, and PK/PD relationships can give your team a strategic edge.

Before your GPCR ligand ever meets its receptor, it meets the enzymes that determine whether it survives long enough to act. Recognizing, predicting, and leveraging these interactions is the essence of enzyme inhibition pharmacology—the framework that connects molecular survival to clinical success.

Every delay in the discovery pipeline compounds into wasted years, lost opportunities, and soaring costs. For drug hunters working at the GPCR interface, the difference between a successful lead and a dead-end candidate often comes down to one overlooked factor: system sensitivity and how we control it.

The difference between orthosteric vs. allosteric mechanisms isn’t just academic — an orthosteric antagonist can hijack receptor physiology, while an allosteric modulator works with the system. That choice determines whether you risk over- or under-dosing, miss safety windows, or miss therapeutic breakthroughs.

GPCRs don’t play fair. Learn how opposing processes, receptor trafficking, and constitutive activity shape drug response—and how to design for them.

Learn how ligand binding kinetics reveal hidden drug effects, improve GPCR assay design, and prevent costly errors in drug discovery pipelines.

Turn assay snapshots into predictions. Models separate orthosteric vs allosteric mechanisms and guide experiments for faster decisions in Terry’s Corner.

Stop guessing at curve shifts. Learn how t-tests, ANOVA & F-tests bring confidence, not noise, to drug discovery decisions.

Think you understand ligand displacement? Think again. This week’s Terry’s Corner blog reveals how allosteric modulators reshape receptor identity—and why conventional binding logic fails in these systems.

Most drug discovery teams chase potency, but miss the variable that often determines real-world success: target residence time. In this expert lecture, Dr. Terry Kenakin explores how restricted diffusion, rebinding, and kinetic dissociation transform in vivo pharmacology, especially when PK and PD diverge. If your leads fail in translation, this may be the insight your pipeline needs.

Don’t let curve shapes deceive you. In this blog, Dr. Terry Kenakin unpacks why dose-response shifts aren’t definitive proof of antagonist mechanism. Learn how binding kinetics—not just appearance—distinguish competitive from non-competitive antagonism, and why assumptions can mislead drug discovery decisions. If your team relies on DR curves to evaluate receptor blockade, this read will sharpen your approach and help you avoid common pitfalls in mechanism interpretation.

From cryptic binding sites to ligand‑specific signaling, uncover how GPCR dynamics redefine drug discovery strategies and decision‑making.

Explore how GPCRs function as dynamic allosteric machines in this expert-level breakdown from Dr. Terry Kenakin. Learn how probe dependence, cryptic binding sites, and conformational changes impact drug discovery and therapeutic design.

Kenakin’s kinetic insights help you translate assay readouts into actionable knowledge that keeps your programs focused and moving efficiently toward clinical relevance.

In Terry Kenakin’s latest lecture from the Emerging Drug Hunter series, he invites you into a thought-provoking reevaluation of one of pharmacology’s most misleading concepts: the myth of high and low-affinity binding sites.