Search Results

reveal recognition motifs for the MRGPRD GPCR Chunyu Wang ,  Yongfeng Liu ,  Marion Lanier ,   Brian K ductal adenocarcinoma, β-blockers and antihistamines: A clinical trial is needed Jillian G Baker ,  Erica K Sloan ,   Kevin Pfleger ,  Peter J McCormick , Cristina Salmerón ,   Paul A Insel PGxDB: an interactive

In modern drug discovery, the promise of precision medicine often collides with the reality of unpredictable pharmacokinetics . Even compounds with pristine target profiles can fail in vivo due to poor absorption, limited tissue distribution, or unanticipated clearance . Although major advances in predictive tools have reduced PK-driven attrition, misconceptions about ADME (absorption, distribution, metabolism, excretion)  persist across discovery teams. Too often, fundamentals are undervalued: in vitro assays are treated as routine checkboxes, and ADME is mistakenly assumed to track with activity or safety. When PK is misunderstood early, Dr. Kenakin argues, every downstream variable becomes distorted —from preclinical modeling to dose selection and late-stage efficacy. In This Session, You’ll Gain Clarity on how ADME governs translational success A deeper understanding of scaffold independence in PK and safety optimization A renewed framework for asking the four core questions of drug movement Debunking the pharmacokinetics Bottleneck Despite technological leaps, pharmacokinetics is still often mischaracterized as a “solved” problem. In the late 20th century, nearly half of investigational drugs failed due to inadequate PK. Predictive in vitro assays have dramatically reduced this attrition—but with success comes complacency . PK errors no longer dominate failure statistics, but fundamental blind spots still derail programs Every therapeutic area—CNS, cardiovascular, GI—faces the same core PK constraints Dr. Kenakin challenges the assumption that “good enough” tools guarantee progress, emphasizing that judgment and experimental framing still matter PK is no longer the bottleneck it once was—but ignoring fundamentals creates rare, high-impact failures . The Independence of Drug Attributes Primary activity, ADME, and safety form three independent axes of drug optimization . Crucially, altering one does not inherently change the others—a principle often overlooked in early discovery. The IGF-1 scaffold example demonstrates how CYP450 liabilities were mitigated without compromising efficacy This independence empowers chemists to optimize safety or PK without sacrificing target engagement Optimization should be modular, not monolithic Medicinal chemistry succeeds fastest when teams stop assuming trade-offs that don’t actually exist. The Four Fundamental Questions of PK All pharmacokinetic strategy reduces to four deceptively simple questions: How much of the administered dose reaches systemic circulation? Where does the drug distribute once inside the body? How long does it persist at the target site? How frequently must it be dosed to maintain effective exposure? Across therapeutic classes, Dr. Kenakin shows that programs fail when these questions are skipped, deferred, or answered implicitly instead of experimentally . Drug-Like Properties: The Real Starting Point PK does not begin at dosing—it begins with physicochemical properties baked into the scaffold . Solubility, lipophilicity (e.g., logP), and polarity govern whether molecules can cross membranes, dissolve in tissues, or survive circulation. Transporter affinity and solubility limits routinely sabotage otherwise strong ligands Effective PK optimization starts with realistic starting points Early property mapping accelerates the design–test–learn cycle Drug discovery is faster when chemistry starts aligned with biology, not fighting it. Absorption: Navigating Barriers to Entry Absorption remains one of the most context-dependent challenges in PK. While parenteral routes bypass absorption barriers, oral and topical delivery require navigating complex biological interfaces. Passive diffusion dominates for many small molecules, but protein binding, transporters, and tissue architecture  play decisive roles Dr. Kenakin highlights predictive in vitro permeation assays  that enable early iteration Absorption failures are rarely about route choice alone—they reflect mismatches between scaffold properties and biological surfaces Distribution: Beyond a Uniform Fluid Model The body is not a homogeneous container. It is a patchwork of semi-permeable compartments  that act as reservoirs, sinks, or barriers. Volume of distribution  provides a quantitative window into tissue partitioning Drugs that sequester into adipose or specialized tissues alter both efficacy and toxicity Dr. Kenakin presents cases where unexpected distribution profiles forced complete strategic pivots Plasma concentration alone is an incomplete proxy for exposure where it matters. Metabolism and Excretion: The Hepatic Engine Once in circulation, drugs encounter hepatic metabolism—primarily driven by cytochrome P450 enzymes —which governs clearance and duration of action. Metabolic conversion often inactivates compounds en route to renal excretion Species differences complicate translation from preclinical models Dr. Kenakin introduces mass-balance thinking and metabolic accounting  to proactively manage liabilities Clearance is not an endpoint—it is a design parameter. Predictive Assays: Assumptions and Opportunities High-throughput PK panels have transformed discovery, but they introduce new risks: overconfidence and black-box interpretation . In vitro–in vivo correlation depends on scaling assumptions and controls CYP inhibition, transporter assays, protein binding, and permeability all carry confounders Data quality hinges on experimental design and interpretive skepticism Tools inform decisions; they do not replace them. ADME as the Engine of Translation True PK mastery reveals its value at the point of translation. Even perfect receptor pharmacology fails if target-site exposure is insufficient or transient . Continuous PK integration —from scaffold design through population modeling— correlates with clinical success Scientists need to “think like a molecule” , tracing its path from administration to excretion Minor ADME adjustments —sometimes a single methyl group— can redefine clinical outcomes PK is the backbone of reproducible, actionable pharmacology. Why Terry’s Corner Terry’s Corner  delivers weekly pharmacology lectures from Dr. Terry Kenakin, monthly AMAs, and a growing on-demand library built around pharmacology's most important principles. Each session re-centers fundamentals, sharpens judgment, and equips scientists to identify problems before they become failures . Designed for pharmacologists, medicinal chemists, and discovery leaders who refuse to rely on assumptions. Forty years of expertise, applied to modern discovery. Explore the full library Or preview what’s inside: Read the latest articles 40 years of expertise at your fingertips : Explore the full library ➤

Eric Trinquet, a veteran innovator behind functional GPCR assays like HTRF and IP-One, believes rigid “You can try, try, try—and fail, fail, fail,” Eric says. Instead of chasing linear progress, Eric encourages young scientists to stay playful longer—embracing Eric and his team rejected the calcium route entirely. Eric is clear: real innovation requires real partnerships.

K. M.; Wheal, A. J.; Goulding, J.; Robers, M. B.; Machleidt, T.; Wood, K. V.; Hill, S. .; Pfleger, K. D. G. Application of BRET to Monitor Ligand Binding to GPCRs. 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. Pharmacol. 2000, 362, 382-391. https://doi.org/10.1007/s002100000315 (7) Jacobson, K. A.

K., Gellman, S. H., Pautsch, A., Steyaert, J., Weis, W. I., & Kobilka, B. K. (2011). M., Manglik, A., Hu, J., Hu, K., Eitel, K., Hübner, H., Pardon, E., Valant, C., Sexton, P. I., Garcia, K. C., Wess, J., & Kobilka, B. K. (2013). D., Tworak, A., Watanabe, K., Pardon, E., Steyaert, J., Kandori, H., Katayama, K., Kiser, P. D., & Palczewski, K. (2023).

During Stage 1 of the project, four promising functionalized structures of P1 demonstrated a K* B However, none of these compounds exhibited a K* B** of less than 100nM* , unlike the functionalized The best compound identified was CELT-58 , which was obtained by combining MFLV18 with Cy5, showing a K* K.; Liu, H.; Koehler, M.; Zhang, C.; Fan, H.; Alsteens, D. K.; Wang, L.; Chung, K. Y.; Fan, H.; Wei, Z.; Zhang, C.

K., & Jacobson, K. A. (2010). Structure-based discovery of A2A adenosine receptor ligands. K., Bouvier, M., & Babu, M. M. (2023). L., Gregory, K. J., White, P. J., Sexton, P. M., Christopoulos, A., & May, L. T. (2016).

To validate that the developed assay is suitable for measuring the K i of different ligands, competition The Log(IC50) change in time was fitted with equation  3  and k given is the weighted average from 3  D.; Hanada, K.; Pagano, R. E.; Miller, L. J. -J.; Veiksina, S.; Kõlvart, K. R.; Min, M.; Kopanchuk, S.; Rinken, A. C.; Chen, K. H.; Bates, M.; Zhuang, X.

K., Das, A. K., Eds.; Elsevier, 2023; Vol. 103, pp 59–103. https://doi.org/10.1016/bs.coac.2023.02.005 .

and mastering drug binding kinetics is essential for pipeline efficiency: How fast a ligand binds (k₁ ) and how long it stays bound (k₂)  can alter therapeutic profiles dramatically, even if two candidates

.; Vemuri, K.; Pu, M.; Qu, L.; Han, G. (3), 750-762.e14. https://doi.org/10.1016/j.cell.2016.10.004 . (5)         Li, X.; Hua, T.; Vemuri, K. -H.; Wu, Y.; Wu, L.; Popov, P.; Benchama, O.; Zvonok, N.; Locke, K.; Qu, L.; Han, G. W.; Iyer, M. 382–389. https://doi.org/10.1021/acs.bioconjchem.7b00680 . (13)      Gazzi, T.; Brennecke, B.; Atz, K. .; Van Der Wel, T.; Mandhair, H.; Honer, M.; Fingerle, J.; Scheffel, J.; Broichhagen, J.; Gawrisch, K.

Pharmaceuticals (Basel, Switzerland), 14(5), 439. https://doi.org/10.3390/ph14050439 Chen, K. K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003). C., Götz, K., Sungkaworn, T., Lohse, M. J., & Calebiro, D. (2016). I., & O'Malley, K. L. (2017). A., Sriram, K., Wiley, S.

assays):  Displacement of specific radiolabeled ligands in CHO, HeLa, or HEK-293 cells, expressed as K References Kumar V, Chunchagatta Lakshman PK, Prasad TK, Manjunath K, Bairy S, Vasu AS, Ganavi B, Jasti

K., Selent, J., Hill, S. J., & Calebiro, D. (2023). M., Kawakami, K., Masureel, M., Maeda, S., Garcia, K. C., von Zastrow, M., Inoue, A., & Kobilka, B. K. (2022). Membrane phosphoinositides regulate GPCR-β-arrestin complex assembly and dynamics.

K., Bouvier, M., & Babu, M. M. (2023). K., Hoppe, N., Huang, X. P., Macdonald, C. B., Mehrota, E., Grimes, P.

K., Strader, D. J., Benovic, J. L., Dohlman, H. G., Frielle, T., Bolanowski, M. A., Bennett, C. K., Hildebrand, P. W., & Skiniotis, G. (2023).

Brian K. Shoichet, Dr. Luc Van Hijfte and Dr. Wendy Young.

receptor (GPCR) pharmacogenomics Miles D Thompson , David Reiner-Link , Alessandro Berghella , Brinda K Family A GPCR Jun Xu , Geng Chen , Haoqing Wang , Sheng Cao , Jie Heng , Xavier Deupi , Yang Du , Brian K

Lin S, Schorpp K, Rothenaigner I, Hadian K. Image-based high-content screening in drug discovery.

extracellular signal-regulated kinases 1/2 (ERK1/2) signaling, p38 signaling, mitochondrial respiration and Na+/K+

Jang W, Senarath K, Feinberg G, Lu S, Lambert NA.

Schlander M, Hernandez-Villafuerte K, Cheng CY, Mestre-Ferrandiz J, Baumann M. Dave K, Gelman H, Thu CT, Guin D, Gruebele M. Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, et al. Truong ME, Bilekova S, Choksi SP, Li W, Bugaj LJ, Xu K, et al.

through G-protein-coupled receptors (GPCRs), fine-tune motoneuron (MN) IME by modulating background K+

hydrogen-deuterium exchange (HDX) mass spectrometry for time-dependent conformational insights (Komolov, K. proteins, presenting an array of effectors that could be recruited to GPCR–β-arrestin complexes (Xiao, K

Research Transcriptome analysis of Schizothorax oconnori (Cypriniformes: Cyprinidae) oocytes: The role of K+

K., Karnik, S. S., Hunyady, L., Luttrell, L. M., & Lefkowitz, R. J. (2003).

This week's highlight includes congrats to: Makaía M Papasergi-Scott, Peter Gmeiner, Brian K Kobilka,

Cell death signaling in Anopheles gambiae initiated by Bacillus thuringiensis Cry4B toxin involves Na+/K+

K ´ onigstorfer, M. Mozhayeva, Y. Sara, T.C. Südhof, and ¨ E.T. Kavalali. 2001.

K., Hoppe, N., Huang, X.-P., Macdonald, C. B., Mehrotra, E., Patrick Rockefeller Grimes, Zahm, A.