Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds

Oppelt, Angela; Kaschek, Daniel; Huppelschoten, Suzanna; Sison-Young, Rowena; Zhang, Fang; Herrmann, Franziska; Malkusch, Sebastian; Krüger, Carmen L.; Meub, Mara; Merkt, Benjamin; Zimmermann, Lea; Schofield, Amy; Jones, Robert; Malik, Hassan; Schilling, Marcel; Heilemann, Mike; Water, Bob van de; Goldring, Christopher E.; Park, B. Kevin; Timmer, Jens; Klingmüller, Ursula

doi:10.1038/s41540-018-0058-z

Cited by 19 publications

(28 citation statements)

References 77 publications

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“…By integrating transcriptome analysis, machine learning, structural analysis, and live cell imaging, the authors showed that the maturation of multiprotein complexes required for IKK activation can be inhibited, thus effectively inhibiting NF-κB signaling. Oppelt et al [ 185 ] used a mathematical model to identify factors — IKK and free cytoplasmic IκBα—that contribute to increased hepatotoxicity caused by the combination of TNF-α and the anti-inflammatory drug diclofenac. They not only proposed a new mathematical model of NF-ĸB but also used it to assess the safety of drugs.…”

Section: Discussionmentioning

confidence: 99%

Systems approaches to investigate the role of NF-κB signaling in aging

Haga

Okada

2022

Biochemical Journal

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The nuclear factor-κB (NF-κB) signaling pathway is one of the most well-studied pathways related to inflammation, and its involvement in aging has attracted considerable attention. As aging is a complex phenomenon and is the result of a multi-step process, the involvement of the NF-κB pathway in aging remains unclear. To elucidate the role of NF-κB in the regulation of aging, different systems biology approaches have been employed. A multi-omics data-driven approach can be used to interpret and clarify unknown mechanisms but cannot generate mechanistic regulatory structures alone. In contrast, combining this approach with a mathematical modeling approach can identify the mechanistics of the phenomena of interest. The development of single-cell technologies has also helped clarify the heterogeneity of the NF-κB response and underlying mechanisms. Here, we review advances in the understanding of the regulation of aging by NF-κB by focusing on omics approaches, single-cell analysis, and mathematical modeling of the NF-κB network.

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Section: Discussionmentioning

confidence: 99%

Systems approaches to investigate the role of NF-κB signaling in aging

Haga

Okada

2022

Biochemical Journal

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“…Targeting the NF-κB pathway by computational approaches has so far been mostly addressed by mathematical, dynamic pathway modeling using ordinary differential equations (ODEs) of the signaling pathway 30 , but the structural biology has not been fully exploited yet. Computational studies have proven to play an integral role in linking theoretical biophysics to the fields of experimental cell biology, clinical pharmacology and medicine.…”

Section: A N U S C R I P Tmentioning

confidence: 99%

Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models

Kanan

Erol

et al. 2019

Journal of Molecular Graphics and Modelling

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Nuclear factor-κB (NF κB) transcription factors represent a conserved family of proteins that regulate not only immune cells, but also heart cells, glial cells and neurons, playing a fundamental role in various cellular processes. Due to its dysregulation in certain cancer types as well as in chronic inflammation and autoimmune diseases, it has recently been appreciated as an important therapeutic target. The aim of this study was to investigate the binding pocket of NF κB (p50/p65) heterodimer complex in association with NF κB inhibitor IκBα to identify potent ligands via fragment-based e-pharmacophore screening. The ZINC Clean Fragments (~2 million) and the Schrodinger's medically relevant Glide fragments library (~670) were used to create the e-pharmacophore models at the potential binding site of the target which was validated by site mapping. Glide/HTVS docking was conducted followed by re-docking of the top 20% fragments by Glide/SP and Glide/XP protocols. The top-85000 Glide XP-docked fragments were used to generate the e-pharmacophore hypotheses. The Otava small molecule library (~260000 drug-like molecules) and additional 85 known NF κB inhibitors were screened against the derived e-pharmacophore models. The top-1000 high-scored molecules, which were well aligned to the e-pharmacophore models, from the Otava small molecule library, were then docked into the binding pocket. Finally, the selected 88 hit molecules and the 85 known inhibitors were analyzed by the MetaCore/MetaDrug™ platform, which uses developed binary QSAR models for therapeutic activity prediction as well as pharmacokinetic and toxicity profile predictions of screening molecules. Ligand selection criteria led to the refinement of 3 potent hit molecules using molecular dynamics (MD) simulations to better investigate their structural and dynamical profiles. The selected hit molecules had a low toxicity and a significant therapeutic potential for heart failure, antiviral activity, asthma and depression, all conditions in which NF κB plays a critical role. These hit ligands were also structurally stable at the NF-κB/IκBα complex as per the MD simulations and MM/GBSA analysis. Two of these ligands (Otava IDs: 1426436 and 6248112) were energetically more favorable and therefore are hypothesized to be more potent. Identifying new potent NF κB/IκBα inhibitors may thus present a novel therapy for inflammation-mediated conditions as well as cancer, facilitating more efficient research, and leading the way to future drug development efforts.

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“…The search for potent and safe NF-κB inhibitors is of paramount importance as it may represent a novel therapeutic strategy for many diseases including inflammatory diseases and viral infections. While the full structural details of NF-κB have not been characterized yet, computational studies have thus far used mathematical modeling and simulation tool to investigate NF-κB and its signaling pathways 34 . Predictions made by various in silico studies which were successfully complemented by wet lab studies have advanced our understanding of NF-κB signaling pathways 35 .…”

Section: Introductionmentioning

confidence: 99%

Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model

Kanan

Shardoub

et al. 2021

Journal of Molecular Graphics and Modelling

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NF-κB is a central regulator of immunity and inflammation. It is suggested that the inflammatory response mediated by SARS-CoV-2 is predominated by NF-κB activation. Thus, NF-κB inhibition is considered a potential therapeutic strategy for COVID-19. The aim of this study was to identify potential anti-inflammation lead molecules that target NF-κB using a quantitative structure-activity relationship (QSAR) model of currently used and investigated anti-inflammatory drugs as the basis for screening. We applied an integrated approach by starting with the inflammation- based QSAR model to screen three libraries containing more than 220,000 drug-like molecules for the purpose of finding potential drugs that target the NF-κB/ IκBα p50/p65 (RelA) complex. We also used QSAR models to rule out molecules that were predicted to be toxic. Only 382 molecules were selected as potentially nontoxic and were analyzed further by short and long molecular dynamic (MD) simulations and free energy calculations. We have discovered five hit ligands with highly predicted anti-inflammation activity and nearly no predicted toxicities which had strongly favorable protein-ligand interactions and conformational stability at the binding pocket compared to a known NF-κB inhibitor (procyanidin B2). We propose these hit molecules as potential NF-κB inhibitors which can be further investigated in pre-clinical studies against SARS-CoV-2 and may be used as a scaffold for chemical optimization and drug development efforts.

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Model-based identification of TNFα-induced IKKβ-mediated and IκBα-mediated regulation of NFκB signal transduction as a tool to quantify the impact of drug-induced liver injury compounds

Cited by 19 publications

References 77 publications

Systems approaches to investigate the role of NF-κB signaling in aging

Systems approaches to investigate the role of NF-κB signaling in aging

Targeting the NF-κB/IκBα complex via fragment-based E-Pharmacophore virtual screening and binary QSAR models

Transcription factor NF-κB as target for SARS-CoV-2 drug discovery efforts using inflammation-based QSAR screening model

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