ArticleNaunyn-Schmiedeberg's archives of pharmacology2013
Simplified models for heterobivalent ligand binding: when are they applicable and which are the factors that affect their target residence time.
Article in Naunyn-Schmiedeberg's archives of pharmacology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 27 citations in OpenAlex.
- Illuminating Neuropeptide Y YACS pharmacology & translational science · 2024Article
- Modular One-Pot Strategy for the Synthesis of Heterobivalent Tracers.ACS medicinal chemistry letters · 2023Article
- Biased, Bitopic, Opioid-Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction.Pharmaceuticals (Basel, Switzerland) · 2022Review
- Induced fit versus conformational selection: From rate constants to fluxes… and back to rate constants.Pharmacology research & perspectives · 2021Article
- Selective CRAF Inhibition Elicits Transactivation.Journal of the American Chemical Society · 2021Article
- Current State of Radiolabeled Heterobivalent Peptidic Ligands in Tumor Imaging and Therapy.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Synthesis and pharmacological evaluation of bivalent tethered ligands to target the mGluBioorganic & medicinal chemistry letters · 2020Article
- Mechanisms of PDZ domain scaffold assembly illuminated by use of supported cell membrane sheets.eLife · 2019Article
- Link between a highMedChemComm · 2018Review
- Distinct in vivo target occupancy by bivalent- and induced-fit-like binding drugs.British journal of pharmacology · 2017Article
- Heterodimerization of Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Leads to Increased MACS omega · 2017Article
- Behaviour of intrinsically disordered proteins in protein-protein complexes with an emphasis on fuzziness.Cellular and molecular life sciences : CMLS · 2017Review
- Cell membranes… and how long drugs may exert beneficial pharmacological activity in vivo.British journal of clinical pharmacology · 2016Review
- On the different experimental manifestations of two-state 'induced-fit' binding of drugs to their cellular targets.British journal of pharmacology · 2016Review
- Selective, rapid and optically switchable regulation of protein function in live mammalian cells.Nature chemistry · 2015Article
- Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High-Affinity Bivalent Ligand.Angewandte Chemie (International ed. in English) · 2015Article
- 'Partial' competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models.British journal of pharmacology · 2015Article
- Synthesis and evaluation of chloramphenicol homodimers: molecular target, antimicrobial activity, and toxicity against human cells.PloS one · 2015Article
- Molecular mechanism of allosteric modulation at GPCRs: insight from a binding kinetics study at the human A1 adenosine receptor.British journal of pharmacology · 2014Article
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1 author at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Bivalent ligands often display high affinity/avidity for and long residence time at their target. Thereto responsible is the synergy that emanates from the simultaneous binding of their two pharmacophores to their respective target sites. Thermodynamic cycle models permit the most complete description of the binding process, and thereto, corresponding differential equation-based simulations link the "microscopic" rate constants that govern the individual binding steps to the "macroscopic" bivalent ligand's binding properties. Present simulations of heterobivalent ligand binding led to an appreciably simpler description thereof. The thermodynamic cycle model can be split into two pathways/lanes that the bivalent ligand can solicit to reach fully bound state. Since the first binding event prompts the still free pharmacophore to stay into "forced proximity" of its target site, such lanes can be looked into by the equations that also apply to induced fit binding mechanisms. Interestingly, the simplest equations apply when bivalency goes along with a large gain in avidity. The overall bivalent ligand association and dissociation will be swifter than via each lane apart, but it is the lane that allows the fastest bidirectional "transit" between the free and the fully bound target that is chiefly solicited. The bivalent ligand's residence time is governed not only by the stability of the fully bound complex but also by the ability of freshly dissociated pharmacophores to successfully rebind. Hence, the presence of a slow-associating pharmacophore could be counterproductive. Yet, a long residence time is unfortunately also responsible for the slow attainment of binding equilibrium.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.