The role of kinetic context in apparent biased agonism at GPCRs

Javitch, Jonathan A.; Klein Herenbrink, Carmen; Sykes, David A.; Donthamsetti, Prashant; Canals, Meritxell; Coudrat, Thomas; Shonberg, Jeremy; Scammells, Peter J.; Capuano, Ben; Sexton, Patrick M.; Charlton, Steven J.; Javitch, Jonathan; Christopoulos, Arthur; Lane, J. Robert

doi:10.1038/ncomms10842

All Outputs (8)

ThermoBRET: A Ligand-Engagement Nanoscale Thermostability Assay Applied to GPCRs** (2023)
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Measurements of membrane protein thermostability reflect ligand binding. Current thermostability assays often require protein purification or rely on pre-existing radiolabelled or fluorescent ligands, limiting their application to established targets... Read More about ThermoBRET: A Ligand-Engagement Nanoscale Thermostability Assay Applied to GPCRs**.

Combined docking and machine learning identify key molecular determinants of ligand pharmacological activity on β2 adrenoceptor (2022)
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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... Read More about Combined docking and machine learning identify key molecular determinants of ligand pharmacological activity on β2 adrenoceptor.

Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor (2019)
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Haloperidol is a typical antipsychotic drug (APD) associated with an increased risk of extrapyramidal side-effects (EPS) and hyperprolactinemia relative to atypical APDs such as clozapine. Both drugs are dopamine D2 receptor (D2R) antagonists, with c... Read More about Structure-Kinetic Profiling of Haloperidol Analogues at the Human Dopamine D2 Receptor.

Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds (2019)
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An increased appreciation of the importance of optimizing drug-binding kinetics has lead to the development of various techniques for measuring the kinetics of unlabeled compounds. One approach is the competition-association kinetic binding method fi... Read More about Investigating the Influence of Tracer Kinetics on Competition-Kinetic Association Binding Assays: Identifying the Optimal Conditions for Assessing the Kinetics of Low-Affinity Compounds.

Binding kinetics of ligands acting at GPCRs (2019)
Journal Article

The influence of drug-receptor binding kinetics has often been overlooked during the development of new therapeutics that target G protein-coupled receptors (GPCRs). Over the last decade there has been a growing understanding that an in-depth knowled... Read More about Binding kinetics of ligands acting at GPCRs.

Reply to ‘Antipsychotics with similar association kinetics at dopamine D2 receptors differ in extrapyramidal side-effects’ (2018)
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Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors (2017)
Journal Article

Atypical antipsychotic drugs (APDs) have been hypothesized to show reduced extrapyramidal side effects (EPS) due to their rapid dissociation from the dopamine D2 receptor. However, support for this hypothesis is limited to a relatively small number o... Read More about Extrapyramidal side effects of antipsychotics are linked to their association kinetics at dopamine D2 receptors.

The role of kinetic context in apparent biased agonism at GPCRs (2016)
Journal Article

Biased agonism describes the ability of ligands to stabilize different conformations of a GPCR linked to distinct functional outcomes and offers the prospect of designing pathway-specific drugs that avoid on-target side effects. This mechanism is usu... Read More about The role of kinetic context in apparent biased agonism at GPCRs.