Irreversible Drugs, Real Control: Design for Durable Target Engagement

Dr. GPCR News
Oct 23
3 min read

Updated: Oct 23

Molecular innovation

This Week’s GPCR Intelligence:

The next edge in discovery isn’t louder exposure—it’s smarter engagement. This week’s Dr. Kenakin from Terry's Corner shows how to tame irreversible drugs so their kinetic power works for you, not against you.

You’ll get a framework to predict duration, penetration, and PK/PD separation—so decisions move faster and risks surface earlier.

Breakthroughs this week: nanomedicines targeting PAR2 for sustained analgesia; Emerging Voices in GPCR Biology; Domain Therapeutics patents new PAR2 antagonists.

🔍 This Week in Dr. GPCR Premium: Sneak Peek

Industry insights: Confo VLAIO grant; Skye CB1 Ph2 miss; Chugai CT-388 in-license; Septerna valuation.

Upcoming events: Membrane-mimetic screening; GPCR Forum 2025; GPCR-TDD Summit Europe.

Career opportunities: Sr. Scientist—In-vitro Pharm; Postdoc roles.

Must-read publications: AT1R β-arrestin bias; UII receptor structure; β2AR constant-pH dynamics.

Terry's Corner – Control Target Engagement—Don’t Chase It with Irreversible Drugs

When binding outlives exposure, everything changes. This feature frames how to define “irreversible” in real systems, anticipate PK/PD separation, and use target turnover to tune duration.

You’ll see why tight binding can backfire on tissue penetration, where k_inact/K_I beats classic Ki, and how to quantify what matters—speed of inactivation and durability of effect.

If your team is designing covalent or tight-binding candidates, these principles reduce surprises and accelerate dose optimization.

You’ll avoid costly missteps by:

Preventing kinetic traps—spot PK/PD decoupling early so washouts and C_max don’t mislead dosing strategy.
Designing for penetration—balance on/off rates to reach inner tissue, not just peripheries.
Quantifying what counts—prioritize k_inact and k_inact/K_I to compare irreversible inhibitors realistically.

🎥 Live AMA with Dr. Kenakin — October 30, 12 PM EST

Join Dr. Kenakin live and bring the questions that keep you thinking. Each AMA feeds directly into next month’s lessons—your real-world challenges shape what comes next.

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🎬 Plus New: Lesson Trailers

Curious about Terry’s Corner before committing? Watch our new trailers for a preview of expert-led GPCR training designed for scientists and drug hunters.

^💎 $2,999/year — the cost of one conference = a year of expert training — Premium Members Enjoy Over 50% Discount at Checkout

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DrGPCR Podcast: Jens Carlsson on Predictive Modeling

Prediction over explanation—that’s the shift.

Jens Carlsson shares how structure-based design, molecular dynamics, and smart collaboration turn models into decisions, with practical guardrails on AlphaFold’s limits. Ideal for scientists who want modeling to guide experiments, not just narrate them.

Value at a glance:

From screens to hits—how to identify novel GPCR ligands with structure-based workflows.
Know the limits—where AI helps and where it still overpromises.
Bridge the aisle—modelers × experimentalists for faster iteration.

Listen to the episode ➤

Why Dr. GPCR Premium Membership Gives You an Edge

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It’s an operating system for discovery decisions, featuring practical frameworks, trusted curations, and a community that accelerates your progress. Staying current is essential as kinetics, structure, and signaling evolve rapidly. Premium keeps you oriented and out of avoidable dead-ends.

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🔹 Why now?

GPCR innovation is accelerating; act on the right signals today to shape tomorrow’s breakthroughs—and avoid delays others won’t see coming