ArticleScientific reports2016
Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists.
Article in Scientific reports, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 45 citations in OpenAlex.
- Symmetric Ligand Binding Pathways and Dual-State Bottleneck in [NiFe] Hydrogenases from Unbiased Molecular Dynamics.The journal of physical chemistry letters · 2025Article
- Residence time in drug discovery: current insights and future perspectives.Pharmacological reports : PR · 2025Review
- C5aR plus MEK inhibition durably targets the tumor milieu and reveals tumor cell phagocytosis.Life science alliance · 2024Article
- Molecular determinants of antagonist interactions with chemokine receptors CCR2 and CCR5.bioRxiv : the preprint server for biology · 2024Article
- Helix 8 in chemotactic receptors of the complement system.PLoS computational biology · 2022Article
- In Vivo Pharmacodynamic Method to Assess Complement C5a Receptor Antagonist Efficacy.ACS pharmacology & translational science · 2022Article
- Emerging Role of C5 Complement Pathway in Peripheral Neuropathies: Current Treatments and Future Perspectives.Biomedicines · 2021Review
- Submolecular probing of the complement C5a receptor-ligand binding reveals a cooperative two-site binding mechanism.Communications biology · 2020Article
- Binding Mode Exploration of B1 Receptor Antagonists' by the Use of Molecular Dynamics and Docking Simulation-How Different Target Engagement Can Determine Different Biological Effects.International journal of molecular sciences · 2020Article
- Preclinical Pharmacokinetics of Complement C5a Receptor Antagonists PMX53 and PMX205 in Mice.ACS omega · 2020Article
- G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action.Pharmacological reviews · 2020Review
- Novel highly potent OXE receptor antagonists with prolonged plasma lifetimes that are converted to active metabolites in vivo in monkeys.British journal of pharmacology · 2020Article
- Partial ligand-receptor engagement yields functional bias at the human complement receptor, C5aR1.The Journal of biological chemistry · 2019Article
- Emerging Roles for G-protein Coupled Receptors in Development and Activation of Macrophages.Frontiers in immunology · 2019Review
- Orthosteric and allosteric action of the C5a receptor antagonists.Nature structural & molecular biology · 2018Article
- Development and validation of a LC-MS/MS assay for pharmacokinetic studies of complement C5a receptor antagonists PMX53 and PMX205 in mice.Scientific reports · 2018Article
- Drug-Target Kinetics in Drug Discovery.ACS chemical neuroscience · 2018Article
- Binding Thermodynamics and Kinetics Calculations Using Chemical Host and Guest: A Comprehensive Picture of Molecular Recognition.Journal of chemical theory and computation · 2018Article
- Pharmacological inhibition of complement C5a-C5aBritish journal of pharmacology · 2017Article
- A novel CCR2 antagonist inhibits atherogenesis in apoE deficient mice by achieving high receptor occupancy.Scientific reports · 2017Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3 nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1 -3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.
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