Bias Isn't Optional. It's Already There - @TerryPharmacologyCorner & Eurofins DiscoverX

Ligand bias is a consequence of allostery. Any compound that binds to a GPCR and changes its conformation will not produce that change uniformly across signaling pathways, and that differential response is bias. Terry Kenakin, Professor of Pharmacology at UNC Chapel Hill, walks through what that means practically: how to detect it, how to quantify it using transducer ratios and the operational model framework, and how drug discovery programs can use it proactively rather than encounter it as an unexplained variable. This session was produced in collaboration with Eurofins DiscoverX, the industry standard for GPCR cell-based assays, as part of an ongoing partnership with Dr. GPCR. The assay platforms referenced throughout this talk are part of the Eurofins DiscoverX portfolio. For more information visit: https://www.ecosystem.drgpcr.com/euro... About Terry Kenakin Terry Kenakin is Professor of Pharmacology at the University of North Carolina at Chapel Hill, with more than 40 years of contributions to receptor pharmacology. He is known for his work on receptor efficacy, functional allostery, and biased agonism, and for applying the operational model, originally developed by Black and Leff, to the quantification of functional selectivity in drug discovery contexts. He is also the scientific creator of Terry's Pharmacology Corner on Dr. GPCR. Sign up for the free newsletter to stay in the know: https://www.ecosystem.drgpcr.com/terr... What You'll Learn ► How ligand bias arises from allosteric probe dependence, and why it is present at every GPCR target regardless of whether a program is designed to detect it ► Why efficacy is better understood as a quality rather than a single quantity, and what a fingerprint of pathway-specific efficacies means for how you select and advance compounds ► How to detect bias using bias plots, a graphical approach that does not require equations and makes differential pathway activation visible from standard assay data ► How to quantify bias using transducer ratios derived from the operational model, with dose-response curves and a spreadsheet as the only required tools ► Why all allosteric modulators, including PAMs and NAMs, inevitably induce bias, and what this means for the efficacy fingerprint of the natural ligand at the same receptor ► What the current state of in vivo translation looks like for biased compounds, and why the relationship between in vitro fingerprints and in vivo outcomes remains an open question Episode Timeline 00:01 Welcome and introduction - the Dr. GPCR and Eurofins DiscoverX collaboration 01:29 Opening: why bias is simpler than its reputation - and already in your program 03:00 Ground rules: bias as inherent allosteric probe dependence at every target 07:00 The assay toolkit - cyclic AMP, calcium, beta-arrestin, internalization, chaperones, and beyond 11:00 Efficacy as quality, not quantity: the 16-opioid clustering experiment from Monash 14:30 What causes bias: ligand-stabilized receptor ensemble states and the Travena 120 angiotensin case 18:00 Proactive exploitation: strengthening beneficial signals and silencing harmful ones across GLP-1, opioids, angiotensin, and kappa opioids 25:00 Retroactive cross-screening: how bias identifies structurally distinct exemplar compounds from a hit set 27:00 Detecting bias: how to build and read a bias plot without models or equations 31:00 Quantifying bias: the operational model, transducer ratios, and a step-by-step walkthrough with GLP-1 agonist data 40:00 The PAM and NAM blind spot: why every allosteric compound changes the bias landscape 42:17 Q&A: statistical thresholds, therapeutic relevance, internalization assays, and orthosteric vs allosteric bias propensity Explore the Dr. GPCR Premium Ecosystem GPCR University brings together curated science, expert sessions, and a community of researchers working at the edge of receptor biology and drug discovery. If this conversation opened a door, step through it. https://www.ecosystem.drgpcr.com/gpcr... #DrGPCR #GPCR #BiasedAgonism #LigandBias #AllostericModulation #DrugDiscovery #ReceptorPharmacology TAGS biased agonism, ligand bias, GPCR pharmacology, receptor signaling, drug discovery, allosteric modulation, beta-arrestin, G protein signaling, receptor pharmacology, assay development, GPCR assays, transducer ratio, biased agonist, functional selectivity, GPCR drug discovery, PAM NAM, Terry Kenakin, pharmacology 🧠 Want deeper GPCR insights? 👉 See upcoming Masterclass sessions https://www.ecosystem.drgpcr.com/gpcr... _____ 🌐 Explore the latest from the Dr. GPCR Ecosystem Discover the newest GPCR masterclass sessions, research discussions, podcasts and expert articles — all in one place. 👉 See the latest content https://www.ecosystem.drgpcr.com