Nuclear factor-kB (NF-kB) is a crucial transcription factor in the signal transduction cascade of the inflammatory signaling. Activation of NF-κB depends on the phosphorylation of IκBα by IκB kinase (IKKβ) followed by subsequent ubiquitination and degradation. This leads to the nuclear translocation of the p50- p65 subunits of NF-κB, 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 IKKβ represents a rational alternative strategy to the current therapies. A computer-aided drug identification protocol was followed to identify novel IKKβ 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 IKKβ inhibitors for their ability to bind and inhibit IKKβ by evaluating their docking energy. Finally, Thioridazinehydrochloride (TDZ), a potent antipsychotic drug against Schizophrenia was selected and its efficiency in inhibiting IκBα protein degradation and NF-κB activation was experimentally validated. Our study has demonstrated that TDZ blocks IκBα protein degradation and subsequent NF-κB activation to inhibit inflammation. Thus, it is a potential repurposed drug against inflammation.

Additional Metadata
Persistent URL dx.doi.org/10.1038/s41598-018-30763-5, hdl.handle.net/1765/109937
Journal Scientific Reports
Citation
Baig, M.S. (Mirza S.), Roy, A. (Anjali), Saqib, U. (Uzma), Rajpoot, S. (Sajjan), Srivastava, M. (Mansi), Naim, A. (Adnan), … Savai, R. (2018). Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. Scientific Reports, 8(1). doi:10.1038/s41598-018-30763-5