Journal
SCIENTIFIC REPORTS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41598-018-30763-5
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Funding
- Department of Biotechnology (DBT) [BT/RLF/Re-entry/26/2013]
- Department of Science and Technology (DST), Government of India under Early Career Research (ECR) Award [ECR/2016/00852]
- Max Planck Society
- Excellence Cluster Cardio-Pulmonary System (ECCPS)
- Verein zur Forderung der Krebsforschung in Giessen e.V.
- Von-BehringRotgen-Stiftung grant
- Rhon Klinikum AG grant
- LOEWE UGMLC grant
- German Center for Lung Research (DZL)
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Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-kappa B depends on the phosphorylation of I kappa B alpha by I kappa B kinase (IKK beta) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50-p65 subunits of NF-kappa B, and further triggers pro-inflammatory cytokine gene expression. Thus, in the need of a more effective therapy for the treatment of inflammatory diseases, specific inhibition of IKK beta represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKK beta inhibitors from a database of over 1500 Food and Drug Administration (FDA) drugs. The best scoring compounds were compared with the already known high-potency IKK beta inhibitors for their ability to bind and inhibit IKK beta by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting I kappa B alpha protein degradation and NF-kappa B activation was experimentally validated. Our study has demonstrated that TDZ blocks I kappa B alpha protein degradation and subsequent NF-kappa B activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.
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