An Online Biased Signaling Atlas

Caroli, Jimmy; Mamyrbekov, Alibek; Harpsøe, Kasper; Gardizi, Sahar; Dörries, Linda; Ghosh, Eshan; Hauser, Alexander S.; Kooistra, Albert J.; Gloriam, David E.

doi:10.21203/rs.3.rs-2155951/v1

Cited by 3 publications

(3 citation statements)

References 35 publications

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“…a coupling atlas integrating major datasets ( 6 ), structure complexes with GPCRs, and interface interactions ( 7 ). Also ArrestinDb ( 8 ) and Biased Signaling Atlas ( 9 ) have been much expanded and are brought forward as separate resources covering complementary aspects of signal transduction while serving dedicated research communities and use cases.…”

Section: Introductionmentioning

confidence: 99%

GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources

Pándy-Szekeres

Caroli

Mamyrbekov

et al. 2022

Nucleic Acids Research

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G protein-coupled receptors (GPCRs) are physiologically abundant signaling hubs routing hundreds of extracellular signal substances and drugs into intracellular pathways. The GPCR database, GPCRdb supports >5000 interdisciplinary researchers every month with reference data, analysis, visualization, experiment design and dissemination. Here, we present our fifth major GPCRdb release setting out with an overview of the many resources for receptor sequences, structures, and ligands. This includes recently published additions of class D generic residue numbers, a comparative structure analysis tool to identify functional determinants, trees clustering GPCR structures by 3D conformation, and mutations stabilizing inactive/active states. We provide new state-specific structure models of all human non-olfactory GPCRs built using AlphaFold2-MultiState. We also provide a new resource of endogenous ligands along with a larger number of surrogate ligands with bioactivity, vendor, and physiochemical descriptor data. The one-stop-shop ligand resources integrate ligands/data from the ChEMBL, Guide to Pharmacology, PDSP Ki and PubChem database. The GPCRdb is available at https://gpcrdb.org.

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Section: Introductionmentioning

confidence: 99%

GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources

Pándy-Szekeres

Caroli

Mamyrbekov

et al. 2022

Nucleic Acids Research

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“…[8][9][10][11] Afterwards, a number of complex biochemical scenarios may occur depending on the cell type where OX1R/OX2R are expressed, but all of the alternative downstream cascades or biased signaling pathways finally lead, through employing different effectors, to cellular influx of Ca 2+ ions. 12,13 Structurally, human OX1R and OX2R share 64% of primary sequence similarity having 425 (47.5 kDa) and 444 (50.7 kDa) amino acids, respectively, which both can be segmented into 15 different parts or domains forming a function complex around the core binding site for OXA/OXB neuropeptides on the extracellular face of the cytoplasmic membrane. 14,15 Nonselective inhibition of OX1R/OX2R by small-molecule antagonists suvorexant, lemborexant or daridorexant (also known as dual orexin receptor antagonists, DORAs), which are currently the only drugs approved by Food Drug Administration (FDA) for clinical application in this therapeutic class, is primarily indicated for specialized treatment of insomnia.…”

Section: Introductionmentioning

confidence: 99%

Computational Analysis of Fully Activated Orexin Receptor 2 Across Various Thermodynamic Ensembles with Surface Tension Monitoring

Dolezal

2024

Preprint

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Molecular dynamics (MD) simulations play a crucial role in understanding dynamic biological processes at nanoscale, yet predicting non-equilibrium phenomena like receptor activation presents significant challenges. In such cases, the primary objective isn't merely achieving stable MD trajectories; rather, it's imperative to remove all artificial restraints in order to unveil suppressed mechanical modes within the simulated systems, and thus advancing computer-aided drug design. In this study, we investigated the stability of the fully activated conformation of the orexin receptor 2 (OX2R) embedded in a pure 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC) bilayer using MD simulations. Various thermodynamic ensembles (i.e. NPT, NVT, NVE, NPAT, µVT and NPγT) were employed to explore the system's dynamics comprehensively. 11 physical quantities, including so called OX2R activation distance, essential protein dynamics, membrane thickness, hydrogen order parameters, and ligand-protein potential energies, across 104 MD trajectories covering 10.4 µs of chemical time were calculated and profoundly analyzed. Special attention was given to assessing surface tension within the simulation box, particularly under NPγT conditions, where 21 nominal surface tension constants were evaluated. Notably, our findings suggest that traditional thermodynamic ensembles like NPT may not adequately control physical properties of the POPC membrane, impacting the plausibility of the OX2R model. In general, the performed study underscores the importance of employing the NPγT ensemble for computational investigations of membrane-embedded receptors, as it effectively maintains zero surface tension in the simulated system. These results offer valuable insights for future research aimed at understanding receptor dynamics and designing targeted therapeutics.

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“…As we reported, compound 3, already lacks binding selectivity towards DOR relative to MOR. It should also be noted that the gpcrMAX assay uses β-arrestin recruitment as its endpoint, which may mask off-target activities for receptors in cases where compound 1 functions as a G-protein-biased agonist.Unfortunately, this novel chemotype did not exhibit substantial G-protein-bias, defined by the GPCRdb as biasfactor ≥5(Kolb et al, 2022;Caroli et al, 2023). While the compounds displayed partial recruitment for β-arrestin 2, the lower potency and efficacy are inherent to the low amplification in this assay system relative to the high amplification of the cAMP assay.…”

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confidence: 95%

Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a NovelδOpioid Receptor-Selective Agonist Chemotype

Meqbil,

Aguilar,

Blaine

et al. 2024

J Pharmacol Exp Ther

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Delta opioid receptors hold potential as a target for neurological and psychiatric disorders, yet no delta opioid receptor agonist has proven efficacious in critical phase II clinical trials. The exact reasons for the failure to produce quality drug candidates for the delta opioid receptor is nuclear. However, it is known that certain delta opioid receptor agonists can induce seizures and exhibit tachyphylaxis. Several studies have suggested that those adverse effects are more prevalent in delta agonists that share the SNC80/BW373U86 chemotype. There is a need to find novel lead candidates for drug development that have improved pharmacological properties to differentiate them from the current failed delta agonists. Our objective in this study was to identify novel delta opioid receptor agonists. We used a beta-arrestin assay to screen a small GPCR-focused chemical library. We identified a novel chemotype of delta opioid receptor agonists, that appears to bind to the orthosteric site based of docking and molecular dynamic simulation. The most potent agonist hit compound is selective for the delta opioid receptor over a panel of 167 other GPCRs, is slightly biased towards G-protein signaling and has antiallodynic efficacy in a complete Freund's adjuvant model of inflammatory pain in C57BL/6 male and female mice. The newly discovered chemotype contrasts with molecules like SNC80 that are highly efficacious betaarrestin recruiters and may suggest this novel class of delta opioid receptor agonists could be expanded on to develop a clinical candidate drug. Significant statementDelta opioid receptors are a clinical target for various neurological disorders, including migraine and chronic pain. Many of the clinically tested delta opioid agonists share a single chemotype, which carries risks during drug development. Through a small-scale high-throughput screening assay, we identified a novel delta opioid receptor agonist chemotype, which may serve as alternative for the current analgesic clinical candidates.

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An Online Biased Signaling Atlas

Cited by 3 publications

References 35 publications

GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources

GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources

Computational Analysis of Fully Activated Orexin Receptor 2 Across Various Thermodynamic Ensembles with Surface Tension Monitoring

Identification of 1,3,8-Triazaspiro[4.5]Decane-2,4-Dione Derivatives as a NovelδOpioid Receptor-Selective Agonist Chemotype

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