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Moro , a medicinal chemist who introduced him to the interplay between molecular structure and biological “It was not just a molecule—it was a partner interacting with a protein or DNA… that opened a new world Studying cancer-related proteins (BCL2 family), he combined NMR and molecular docking to explore drug Terry Kenakin. ________ Keyword Cloud: #GPCRresearch #DrugDiscovery #ComputationalChemistry #MolecularModeling #MolecularDynamics #AlphaFold #StructuralBiology #InSilicoBiology

such applications, however, is a clearer understanding of how these drugs exert their effects at the molecular Here we review the current knowledge regarding the molecular details of psychedelic drug actions and

August 2022 "Psychedelic research across different disciplines and biological levels is growing at a remarkably fast pace. In the prospect of a psychedelic drug becoming again an approved treatment, much of these efforts have been oriented toward exploring the relationship between the actual psychedelic effects and those manifestations of therapeutic interest. Considering the central role of the serotonin 5-HT2A receptor in the distinct effects of psychedelics in human psyche, neuropharmacology sits at the center of this debate and exploratory continuum. Here we discuss some of the most recent findings in human studies and contextualize them considering previous preclinical models studying phenomena related to synaptic plasticity. A special emphasis is placed on knowledge gaps, challenges, and limitations to evaluate the underpinnings of psychedelics' potential antidepressant action." Read more at the source #DrGPCR #GPCR #IndustryNews

Terry Kenakin dismantles 100 years of receptor theory and introduces you to a dynamic new framework: Molecular Step into Terry’s Vault and explore “Molecular Dynamics”—where expert drug hunters forge the future. Unlock “Molecular Dynamics” Now

Through (un)biased molecular dynamics simulations and mutagenesis experiments, we show that TM2 rearrangement

high-resolution structures of CB1 receptor in different functional states have significantly improved our molecular

Targeting rhodopsin with small molecule chaperones to improve the folding and stability of the mutant This review provides an update on the current knowledge regarding small molecule compounds that have

GPCR Symposia Join us on June 7th for our next symposium on Structural and Molecular Insights into GPCR their name to Nxera Domain Therapeutics to participate at premier investor and healthcare conferences Montana Molecular is joining the BioTools Innovator program GPCR Events, Meetings, and Webinars May 13 - 17, physiology, optical imaging, substance use disorder, pharmacology Research Fellow Postdoctoral Fellow – Molecular

structures are hard to determine experimentally due to poor expression and the volatility of odorant molecules “…now you have a plethora of 400 models that you can start with molecular dynamics, docking, virtual AlphaFold #GPCRdata #DrugDiscovery #OlfactoryReceptors #StructuralBiology #ArtificialIntelligence #MolecularDynamics #ComputationalBiology #MolecularModeling

Though most of these variants exhibit a loss of function, the molecular defects caused by these underlying However, the magnitude of the response to this molecule varies considerably across this spectrum of mutations

October 2022 Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Here, we have implemented an optimized approach of combining the data derived from steered molecular

To elucidate the molecular mechanisms responsible for these effects of RNA editing, we present four active-state

October 2022 "While the role of G-protein-coupled receptors (GPCR) in cancer is acknowledged, their underlying signaling pathways are understudied. Protease-activated receptors (PAR), a subgroup of GPCRs, form a family of four members (PAR1-4) centrally involved in epithelial malignancies. PAR4 emerges as a potent oncogene, capable of inducing tumor generation. Here, we demonstrate identification of a pleckstrin-homology (PH)-binding motif within PAR4, critical for colon cancer growth. In addition to PH-Akt/PKB association, other PH-containing signal proteins such as Gab1 and Sos1 also associate with PAR4. Point mutations are in the C-tail of PAR4 PH-binding domain; F347 L and D349A, but not E346A, abrogate these associations. Pc(4-4), a lead backbone cyclic peptide, was selected out of a mini-library, directed toward PAR2&4 PH-binding motifs. It effectively attenuates PAR2&4-Akt/PKB associations; PAR4 instigated Matrigel invasion and migration in vitro and tumor development in vivo. EGFR/erbB is among the most prominent cancer targets. AYPGKF peptide ligand activation of PAR4 induces EGF receptor (EGFR) Tyr-phosphorylation, effectively inhibited by Pc(4-4). The presence of PAR2 and PAR4 in biopsies of aggressive breast and colon cancer tissue specimens is demonstrated. We propose that Pc(4-4) may serve as a powerful drug not only toward PAR-expressing tumors but also for treating EGFR/erbB-expressing tumors in cases of resistance to traditional therapies. Overall, our studies are expected to allocate new targets for cancer therapy. Pc(4-4) may become a promising candidate for future therapeutic cancer treatment." Read more at the source #DrGPCR #GPCR #IndustryNews

September 2022 "G protein‐coupled receptors (GPCRs) are valuable therapeutic targets for many diseases. A central question of GPCR drug discovery is to understand what determines the agonism or antagonism of ligands that bind them. Ligands exert their action via the interactions in the ligand binding pocket. We hypothesized that there is a common set of receptor interactions made by ligands of diverse structures that mediate their action and that among a large dataset of different ligands, the functionally important interactions will be over‐represented. We computationally docked ~2700 known β2AR ligands to multiple β2AR structures, generating ca 75 000 docking poses and predicted all atomic interactions between the receptor and the ligand. We used machine learning (ML) techniques to identify specific interactions that correlate with the agonist or antagonist activity of these ligands. We demonstrate with the application of ML methods that it is possible to identify the key interactions associated with agonism or antagonism of ligands. The most representative interactions for agonist ligands involve K972.68×67, F194ECL2, S2035.42×43, S2045.43×44, S2075.46×641, H2966.58×58, and K3057.32×31. Meanwhile, the antagonist ligands made interactions with W2866.48×48 and Y3167.43×42, both residues considered to be important in GPCR activation. The interpretation of ML analysis in human understandable form allowed us to construct an exquisitely detailed structure‐activity relationship that identifies small changes to the ligands that invert their pharmacological activity and thus helps to guide the drug discovery process. This approach can be readily applied to any drug target." Read more at the source #DrGPCR #GPCR #IndustryNews

December 2021 Perkins’ Head of Molecular Endocrinology and Pharmacology, Professor Kevin Pfleger, was

Recent structural studies shed light on the molecular mechanisms involved in GPCR-arrestin coupling,

of in silico and in vitro results clarifies sequence-function relationships and proposes functional molecular

A2A adenosine receptor (A2AAR), a class A G protein-coupled receptor (GPCR) for 19F-NMR and single-molecule

two C5aR receptors C5aR1 and C5aR2 we explained differences between their signaling pathways on the molecular By means of molecular dynamics we explained why C5aR2 cannot transduce signal through the G protein pathway

Here, we use molecular metadynamics computations to predict the mechanism by which the inactive GP induces

We also synthesized a series of small molecule ligands which acted as selective agonists for ACKR3 as Using select point mutations, we studied the molecular characteristics that determine the ability of small molecules to activate ACKR3 receptors, revealing a key role for the deeper binding pocket composed novel selective ligands for ACKR3 were discovered and the site of interactions between these small molecules

August 2022 "Single particle cryogenic-electron microscopy (cryo-EM) is used extensively to determine structures of activated G protein-coupled receptors (GPCRs) in complex with G proteins or arrestins. However, applying it to GPCRs without signaling proteins remains challenging because most receptors lack structural features in their soluble domains to facilitate image alignment. In GPCR crystallography, inserting a fusion protein between transmembrane helices 5 and 6 is a highly successful strategy for crystallization. Although a similar strategy has the potential to broadly facilitate cryo-EM structure determination of GPCRs alone without signaling protein, the critical determinants that make this approach successful are not yet clear. Here, we address this shortcoming by exploring different fusion protein designs, which lead to structures of antagonist bound A2A adenosine receptor at 3.4 Å resolution and unliganded Smoothened at 3.7 Å resolution. The fusion strategies explored here are likely applicable to cryo-EM interrogation of other GPCRs and small integral membrane proteins." Read more at the source #DrGPCR #GPCR #IndustryNews

Elevate Your GPCR Science with Essential Frameworks for Precision Drug Discovery: An Insight into Advanced Strategies for Targeted Therapeutics. Welcome back GPCR lovers, In pharmacology, the wrong interpretation of antagonist behavior can derail your conclusions, your experiments, and even your program’s credibility. That’s why mastering competitive vs non-competitive antagonism isn’t optional — it’s essential for accurate, defensible science. This week, Terry’s Corner takes you beyond curve shapes into the kinetic and mechanistic realities that separate surface-level analysis from true expertise. Breakthroughs this week: FFA4 receptor signaling controls lipolysis at lipid droplets; novel atypical GPCR-arrestin complexes; Lilly's oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal Phase 3 trials in adults with obesity. 🔍 This Week in Premium: Sneak Peek A quick look at the curated intelligence our Premium members are using to stay ahead this week: Industry insights:  The latest on how AI is being used to unlock elusive GPCR targets, financial results from Neurocrine Biosciences, and a deep dive into Crinetics Pharmaceuticals’ oral acromegaly drug. We’re also tracking major pipeline clearouts and the competitive landscape for oral GLP-1 drugs. Upcoming events:  An exclusive preview of the “neuroGPCR: G protein coupled receptor signaling in its physiological cellular context” symposium and our featured talk at the upcoming Discovery on Target 2025 conference. Career opportunities:  A curated list of new positions, including a Research Associate, a Senior Research Scientist, and a Post-doctoral Researcher position focused on GPCRs and Mitochondria. Must-read publications:  New insights on RGS protein modulation, GRK2-biased β₂AR signaling, and the distinct role of GRK3 in platelet activation. We’ve also highlighted the latest research on non-canonical internalization mechanisms of mGlu receptors and the intrinsic signaling bias of GPR52. Terry's Corner - Demystifying Antagonism: The Key to Precision Drug Discovery Understanding the nuances of competitive versus non-competitive antagonism is a cornerstone of effective drug discovery. Without a solid grasp of these concepts, scientists risk misinterpreting critical data, leading to flawed decisions and wasted resources. This week in Terry’s Corner , we go beyond the dose-response curves to explore the kinetic and pharmacologic signatures of antagonism. Dr. Kenakin’s expert guidance provides a clear framework for distinguishing these mechanisms and avoiding common pitfalls that can derail a program. Don't let misconceptions about receptor binding kinetics slow your progress—gain the clarity you need to move forward with confidence. Solve the problem of misinterpreting your data by understanding how slow-offset kinetics can mimic classical patterns, leading to incorrect mechanistic assignments. Gain a competitive edge by asking the right questions about binding kinetics and experimental constraints, ensuring your analysis is robust and your decisions are sound. Avoid the professional threat of flawed data interpretations that can lead to costly dead ends and missed opportunities in your drug discovery program. Premium Members get 50%+ discount when they join Terry’s Corner. Sharpen your discovery decisions ➤ Yamina's Consulting Corner - Building Your GPCR Program for Breakthroughs, Not Breakdowns In the fast-paced world of GPCR drug discovery, the "go fast" mindset can often lead to costly breakdowns. Yamina’s Corner tackles the critical disconnect between brilliant science and operational strategy, revealing why throwing more money and people at a problem is a multi-million dollar mistake. This week, we introduce a new series, "The GPCR Precision Blueprint," which provides a systematic framework to ensure your science, strategy, and execution are seamlessly aligned. Learn how to transform your program from a series of disconnected efforts into a predictable, de-risked pathway to success. Solve the problem of a fragmented approach by learning how to build a unified system where every scientific detail and strategic decision aligns. Gain a competitive edge by transforming your GPCR data from chaos into a strategic asset, enabling faster, more confident decision-making. Avoid the professional threat of financial friction and missed investment opportunities by learning to translate operational precision into a compelling narrative for stakeholders. Three takeaways from this week’s feature: Stop firefighting:  Learn why solving isolated problems burns capital without fixing root causes. Bridge science and strategy:  Ensure data and decision-making align with funding and milestones. Build predictable success:  Use a repeatable improvement framework to turn operational chaos into precision execution. Read the full article here ➤ Insights from the Field: The Next Wave of GPCR Drug Discovery The 20th annual GPCR-Based Drug Discovery conference is where the future of GPCR therapies will be defined. If you’re not there, you’re missing out on the next wave of allosteric modulators, biased ligands, and computational targeting. This event is a critical opportunity to stay informed, but the real advantage lies in applying these insights to your work. Our weekly curated news and expert frameworks provide the actionable intelligence you need to make sense of these trends and integrate them into your own research. Solve the problem of information overload by getting a curated summary of the key talks and discussions from the event. Gain a competitive edge by staying on top of the latest breakthroughs in allostery, biased signaling, and computational pharmacology. Avoid the professional threat of falling behind your peers by accessing the same insights that are driving the next generation of drug discovery. Register and join your colleagues in September ➤ Why Dr. GPCR Premium Membership Gives You an Edge In a world filled with noise, Dr. GPCR Premium Membership delivers curated, noise-free intelligence every week. We provide deep-dive expert lessons, classified industry news, priority event alerts, job opportunities, and insider commentary—all designed to help you move faster, smarter, and with greater confidence. This isn’t just information; it’s a strategic framework for your career. Our content is meticulously vetted and organized to provide clarity and actionable insights that you can apply immediately to your work, helping you avoid costly missteps and capitalize on emerging opportunities. FAQ 🔹 What’s included? The complete Weekly News digest, curated jobs, upcoming events, classified GPCR publications, exclusive on-demand expert frameworks, and member-only discounts. 🔹 Who is it for? 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Gain the insights, tools, and connections you need to excel in your field and make your mark. Keywords: GPCR, drug discovery, pharmacology, antagonism, competitive, non-competitive, Terry's Corner, Yamina's Corner, biotech, systems thinking, signal transduction, operational excellence, drug development, pharmaceutical, scientific career Hashtags: #DrGPCR #GPCR #DrugDiscovery #Pharmacology #Biotech #GPCRNews #Science #DrugDevelopment

Molecular dynamics simulations support the local conformational flexibilities and different stabilities

However, the underlying molecular mechanism of the enhanced sensitivity or toxicity of amitraz to mutated Here, molecular dynamics simulations are employed to explore the implied mechanism of the enhanced sensitivity

Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor

October 2022 "Single-molecule counting techniques enable a precise determination of the intracellular in receptor signaling came from ensemble biochemical and biophysical assays, innovations in single-molecule Here, we review recent developments in single-molecule counting with a focus on photobleaching step counting and the emerging technique of quantitative single-molecule localization microscopy-with a particular

Moreover, molecular docking was applied to valid the important interactions between the ingredients and Moreover, molecular docking results showed that Polygalaxanthone III, Girinimbine and Pachymic acid performed

The most diverse and common molecular target of drug medicines is G protein-coupled receptors (GPCRs) prototypical allosteric protein’ [21, 26, 27] because they are regulated in this fashion by ions, small molecules others, could have impacted the results of previous studies determining the 5-HT2AR structure, its molecular WIREs Computational Molecular Science. 2021;11(6):e1529. 23.         Molecules. 2020;25(24). 52.         Teng X, Chen S, Wang Q, Chen Z, Wang X, Huang N, et al.

Therefore, it is imperative to understand the precise molecular mechanism of H2R biology.