The importance of binding kinetics and drug–target residence time in pharmacology

Knockenhauer, Kevin E.; Copeland, Robert A.

doi:10.1111/bph.16104

Cited by 17 publications

(17 citation statements)

References 71 publications

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“…The two-step induced fit model 42 may explain the pseudoirreversible inhibition. In this model, stable binding of a drug with its target occurs via a two-step mechanism: in the first step, binding to the target forms an encounter complex; then, in the second step, a conformational change of the complex occurs and strengthens the drug binding to the target.…”

Section: Discussionmentioning

confidence: 99%

Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonist

Maruyama

Ohsawa

Suzuki

et al. 2023

Preprint

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Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. To find potent S1PR1 antagonists, identification of the structural basis for drug efficacy is important. Here, we synthesized a novel antagonist, KSI-6666, that persistently inhibits S1PR1 activity and effectively suppresses pathogenic inflammation. Metadynamics simulation suggested that the interaction of a benzene ring moiety in KSI-6666 with a methionine residue in the ligand-binding pocket of S1PR1 inhibits the dissociation of KSI-6666 from S1PR1, generating a metastable binding state. Consistently,in vitrofunctional and mutational analyses revealed that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the methionine residue of the protein and substituents on the distal benzene ring of KSI-6666. Moreover,in vivostudy suggested that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666. These findings will contribute to the rational design of potent S1PR1 antagonists for the treatment of inflammatory disorders.

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Section: Discussionmentioning

confidence: 99%

Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonist

Maruyama

Ohsawa

Suzuki

et al. 2023

Preprint

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“…Indeed, leveraging these advantages has led to a resurgence of covalent inhibitors . One such advantage is the prolonged residence time of the inhibitor in the target protein . A second is the ability to inhibit “undruggable” targets .…”

Section: Design Of Noncovalent and Covalent Inhibitorsmentioning

confidence: 99%

“…Although slow off-kinetics improve residence time, faster rates may be more suited in certain circumstances . Extensive reviews on slow-binding kinetics and residence time have previously been written concerning drug-design. ,− Since the intention for developing reversible covalent inhibitors is to reduce off-target effects by taking advantage of reversible kinetics, the residence times of the inhibitor with its on- and off-target enzymes should be optimized. , These experiments were performed both in the development of the BTK inhibitor rilzabrutinib and JAK3 RCIs The binding kinetics of the inhibitor match that of reversible covalent inhibitors.…”

Section: General Considerations For Developing Reversible Covalent In...mentioning

confidence: 99%

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Patel,

Huma,

Duncan

2024

ACS Chem. Biol.

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Covalent inhibition has seen a resurgence in the last several years. Although long-plagued by concerns of off-target effects due to nonspecific reactions leading to covalent adducts, there has been success in developing covalent inhibitors, especially within the field of anticancer therapy. Covalent inhibitors can have an advantage over noncovalent inhibitors since the formation of a covalent adduct may serve as an additional mode of selectivity due to the intrinsic reactivity of the target protein that is absent in many other proteins. Unfortunately, many covalent inhibitors form irreversible adducts with off-target proteins, which can lead to considerable side-effects. By designing the inhibitor to form reversible covalent adducts, one can leverage competing on/off kinetics in complex formation by taking advantage of the law of mass action. Although covalent adducts do form with off-target proteins, the reversible nature of inhibition prevents accumulation of the off-target adduct, thus limiting side-effects. In this perspective, we outline important characteristics of reversible covalent inhibitors, including examples and a guide for inhibitor development.

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“…In particular, the time a drug spends in contact with its biological target (so-called residence time) is now considered a key parameter for optimization because there is some evidence that it can predict drug efficacy in vivo and thus demonstrate the pharmacological significance of the biotarget. [27][28][29] 4. Some biotargets are species-specific.…”

Section: Cvd and Multitargetingmentioning

confidence: 99%

Multitargeting in cardioprotection: An example of biaromatic compounds

Mokrov

2023

Archiv der Pharmazie

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A multitarget drug design approach is actively developing in modern medicinal chemistry and pharmacology, especially with regard to multifactorial diseases such as cardiovascular diseases, cancer, and neurodegenerative diseases. A detailed study of many well‐known drugs developed within the single‐target approach also often reveals additional mechanisms of their real pharmacological action. One of the multitarget drug design approaches can be the identification of the basic pharmacophore models corresponding to a wide range of the required target ligands. Among such models in the group of cardioprotectors is the linked biaromatic system. This review develops the concept of a “basic pharmacophore” using the biaromatic pharmacophore of cardioprotectors as an example. It presents an analysis of possible biological targets for compounds corresponding to the biaromatic pharmacophore and an analysis of the spectrum of biological targets for the five most known and most studied cardioprotective drugs corresponding to this model, and their involvement in the biological effects of these drugs.

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The importance of binding kinetics and drug–target residence time in pharmacology

Cited by 17 publications

References 71 publications

Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonist

Pseudoirreversible inhibition elicits persistent efficacy of a sphigosine-1-phosphate receptor-1 antagonist

Reversible Covalent Inhibition─Desired Covalent Adduct Formation by Mass Action

Multitargeting in cardioprotection: An example of biaromatic compounds

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