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Not because small-molecule chemistry is weaker, but because a small molecule, by definition, occupies Difficult, for a reason that is structural rather than chemical. It is that allosteric chemistry has a structural advantage when the goal is stabilizing an active state small-molecule agonist program encounters at a family B GPCR may be a feature of the geometry, not a flaw in the chemistry Subscribe to The Kenakin Brief today ➤ Check out the YouTube Channel. https://www.youtube.com/@TerryPharmacologyCorner

A medicinal chemist by training, he has spent his career moving between academia and industry, building Drug Discovery Summit — Exclusive DrGPCR Discount Use the exclusive DrGPCR discount code DRGPCR10 at checkout

Standardized Kd measurements enable comparative analysis of affinity distributions and chemical space chatting over coffee — and hoping this becomes a reality in the future." — Anita Nivedha, Computational Chemist

Versus Degradation: The CCR5 Example The therapeutic stakes of this distinction are illustrated by chemokine

.”— Jay, Chemosensory Research Investigator Why Terry’s Corner Terry’s Corner is where frameworks like

Two examples of this include the opioid and chemokine GPCR receptors. For chemokine receptors in inflammation, biased signaling  at CCR5 has been studied as a means of modulating

Chemistry identifies molecules. Biology reveals targets. Chemists Make The Drugs Drug discovery is fundamentally a team sport . But chemists transform that data into molecules capable of becoming medicines. Kenakin often recalls advice from Nobel laureate James Black: Chemists make the drugs. chemists, for example, instinctively avoid known toxicophores —chemical groups associated with safety

advanced to phase II clinical trials for various cancers, particularly in combination with other immune checkpoint PKI values were derived from pIC50 values using the Cheng-Prusoff equation. 3 The pK i values display As a proof of concept, the study shows that Celtarys’ chemistry can be translated into NanoBRET ® TE Chem. 2000, 43 (23), 4359–4362. https://doi.org/10.1021/jm0009843 . (4) Jacobson, K. Chem. 2009, 52 (13), 3994–4006. https://doi.org/10.1021/jm900413e . (6) Klotz, K.-N.

These scientists come from diverse fields such as medicine, agriculture, industrial chemicals, and data The C5a anaphylatoxin chemotactic receptor 1, also known as CD88, is part of the rhodopsin family of The final pharmacophore is derived from a set of at least 3-5 different chemical scaffolds. Specific binding of the most promising fluorescent antagonists in Chem 1 cell lines. Chem.

They stall when chemistry, modeling, and pharmacology drift apart.

It can redirect chemistry strategy, distort translational assumptions, and conceal liabilities that emerge 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 Strategic discipline means: Screening liabilities early Integrating chemistry insights immediately Avoiding

The math checks out.

Terry Kenakin walks through the core early assays that protect your chemistry, budget, and timeline.

robust toxicology In Silico Toxic Signals Advancements in computational screening enable teams to avoid chemotypes acknowledges the increasing utility of in silico alerts in early decision-making, arming medicinal chemists

and tell us what you need ➤ Terry’s Corner—Basic Pharmacokinetics Pharmacokinetics isn’t a late-stage checkbox—it

Too often, fundamentals are undervalued: in vitro assays are treated as routine checkboxes, and ADME demonstrates how CYP450 liabilities were mitigated without compromising efficacy This independence empowers chemists PK without sacrificing target engagement Optimization should be modular, not monolithic Medicinal chemistry points Early property mapping accelerates the design–test–learn cycle Drug discovery is faster when chemistry Designed for pharmacologists, medicinal chemists, and discovery leaders who refuse to rely on assumptions

The moment when clarity is cheapest, alignment is easiest, and impact is highest .

When priorities are explicit, execution accelerates because teams no longer need constant alignment checks

Intellectual property is not a checkbox.

When teams adopt structured decision cycles, consistent narrative checkpoints, and predictable timeline repeatable communication rhythm: internal alignment weekly cross-functional integration biweekly investor check-ins

Kenakin outlines a pragmatic checklist for producing reliable orthosteric binding measurements: Cell

✅ FDA approval is not a documentation checkpoint. It’s a strategic filter. However, that sequence conceals a significant flaw; it treats FDA approval as the  final checkpoint , But approval is not a checkpoint. ✅ It’s a strategic mirror.

conformations, and non-specific interactions introduce noise at precisely the stage where medicinal chemistry SCRAs—although often known for their undesired toxicological profile—offer a chemically diverse set of Furthermore, image-based data provide an additional check against off-target cytotoxicity or morphological Ki values were then calculated using the Cheng–Prusoff equation, with CELT-331 parameters fully reported European Journal of Medicinal Chemistry, 46(2), 547–555.

GPCR Podcast: Chemical Probes for GPCR Imaging with Dr. His work shows why chemical design can outperform antibodies and how rigorous assay validation bridges chemistry and biology effectively.

But behind the polite nods, your audience is checking out.

Kenakin  drew a sharp contrast between chemically reactive irreversible inhibitors and pseudo-irreversible Ranking Partial Agonists Without Losing Meaning Chemists want a single number. These GPCR pharmacology insights are essential for directing chemistry toward the property that actually

automated microscopy, multiplexed imaging, and computational analysis to evaluate cellular responses under chemical

Episode #177 The Experiment That Was Never Meant to Succeed When David Hodson’s lab teamed up with chemist Hodson: physiology, disease context, and imaging logic JB: chemistry, ligand engineering, mechanistic Collaboration, Chemistry, and the Pivot That Changed the Project Goal:  Develop a photo-switchable GPCR

Enter a long-term collaboration with chemist Dr.