Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

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

• Baig, M. S.
• Roy, A.
• Saqib, U.
• Rajpoot, S.
• Srivastava, M.
• Naim, A.
• Liu, D.
• Saluja, R.
• Faisal, S. M.
• Pan, Q.
• Turkowski, K.
• Darwhekar, G. N.
• Savai, R.