Optimized Target Residence Time: Type I Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R‐Spine

Wentsch, Heike K.; Walter, Niklas M.; Bührmann, Mike; Mayer‐Wrangowski, Svenja; Rauh, Daniel; Zaman, Guido J.R.; Willemsen-Seegers, Nicole; Buijsman, Rogier C.; Henning, Melanie; Dauch, Daniel; Zender, Lars; Laufer, Stefan

doi:10.1002/anie.201701185

Cited by 21 publications

(24 citation statements)

References 24 publications

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“…More recently, novel p38 MAPK inhibitors including 36 and 37 have been reported to target both active and inactive states of p38 MAPK for the increased target residence time. They are made up of glycine flip-inducing moieties and binders interacting with the R-spine, which make the compounds have excellent kinase selectivities, significantly potent activities on the enzyme level and in the cell based assay ( Figure 11 ) [ 162 ]. The use of potent and selective p38 MAPK inhibitors would further reveal their potential for the treatment of AD and reduced off-target effects.…”

Section: Discussionmentioning

confidence: 99%

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

2017

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P38 mitogen-activated protein kinase (MAPK) is a crucial target for chronic inflammatory diseases. Alzheimer’s disease (AD) is characterized by the presence of amyloid plaques and neurofibrillary tangles in the brain, as well as neurodegeneration, and there is no known cure. Recent studies on the underlying biology of AD in cellular and animal models have indicated that p38 MAPK is capable of orchestrating diverse events related to AD, such as tau phosphorylation, neurotoxicity, neuroinflammation and synaptic dysfunction. Thus, the inhibition of p38 MAPK is considered a promising strategy for the treatment of AD. In this review, we summarize recent advances in the targeting of p38 MAPK as a potential strategy for the treatment of AD and envision possibilities of p38 MAPK inhibitors as a fundamental therapeutics for AD.

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Section: Discussionmentioning

confidence: 99%

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

2017

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“…34 Other examples include antagonists of the muscarinic M3 receptor, 35 antagonists of the chemoattractant receptor-homologous molecule CRTh2/DP2, 36 and inhibitors of p38α MAP kinase. 37 The second major misconception is that if a compound has similar IC 50 values for two different proteins, the drug-target and an off-target protein associated with unwanted side-effects, then the compound has no selectivity. Indeed, the compound has no thermodynamic selectivity, but if the k on and k off values differ between the two targets, it can still have kinetic selectivity.…”

Section: The Thermodynamics and Kinetics Of Drug–target Interactionsmentioning

confidence: 99%

Drug–Target Kinetics in Drug Discovery

Tonge

2017

ACS Chem. Neurosci.

223

235

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The development of therapies for the treatment of neurological cancer faces a number of major challenges including the synthesis of small molecule agents that can penetrate the blood brain barrier (BBB). Given the likelihood that in many cases drug exposure will be lower in the CNS than in systemic circulation, it follows that strategies should be employed that can sustain target engagement at low drug concentration. Time dependent target occupancy is a function of both the drug and target concentration as well as the thermodynamic and kinetic parameters that describe the binding reaction coordinate, and sustained target occupancy can be achieved through structural modifications that increase target (re)binding and/or that decrease the rate of drug dissociation. The discovery and deployment of compounds with optimized kinetic effects requires information on the structure-kinetic relationships that modulate the kinetics of binding, and the molecular factors that control the translation of drug-target kinetics to time-dependent drug activity in the disease state. This review first introduces the potential benefits of drug-target kinetics, such as the ability to delineate both thermodynamic and kinetic selectivity, and then describes factors, such as target vulnerability, that impact the utility of kinetic selectivity. The review concludes with a description of a mechanistic PK/PD model that integrates drug-target kinetics into predictions of drug activity.

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“…In this context, we have previously reported that among p38α MAPK inhibitors, the type I½ inhibitor regulatory-spine (R-spine) interaction is important for increased target residence time 26 – 28 . However, these type I½ inhibitors have not been studied by the means of long timescale simulations to date and a precise understanding of the underlying mechanisms is still incomplete.…”

Section: Introductionmentioning

confidence: 99%

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

et al. 2022

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Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.

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Optimized Target Residence Time: Type I Inhibitors for p38α MAP Kinase with Improved Binding Kinetics through Direct Interaction with the R‐Spine

Cited by 21 publications

References 24 publications

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Recent Advances in the Inhibition of p38 MAPK as a Potential Strategy for the Treatment of Alzheimer’s Disease

Drug–Target Kinetics in Drug Discovery

Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

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