Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.

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

SUBMITTER: Baig MS 

PROVIDER: S-EPMC6102213 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature