Repurposing Thioridazine (TDZ) as an anti-inflammatory agent.
Mirza S BaigAnjali RoyUzma SaqibSajjan RajpootMansi SrivastavaAdnan NaimDongfang LiuRohit SalujaSyed M FaisalMaikel P PeppelenboschKati TurkowskiGajanan N DarwhekarSoni Savai PullamsettiPublished in: Scientific reports (2018)
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.
Keyphrases
- nuclear factor
- oxidative stress
- signaling pathway
- lps induced
- toll like receptor
- gene expression
- pi k akt
- transcription factor
- anti inflammatory
- inflammatory response
- adverse drug
- dna methylation
- drug administration
- human health
- cell proliferation
- molecular dynamics simulations
- amino acid
- protein kinase
- tyrosine kinase
- electronic health record
- drug discovery