Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

Area of Science:

• Molecular Biology
• Pharmacology
• Drug Discovery

Background:

• Nuclear factor-kB (NF-kB) is a key transcription factor in inflammatory signaling.
• NF-kB activation involves IκBα phosphorylation by IκB kinase (IKKβ), leading to pro-inflammatory cytokine gene expression.
• Targeting IKKβ offers a rational strategy for inflammatory disease therapy.

Purpose of the Study:

• To identify novel IKKβ inhibitors using a computer-aided drug design approach.
• To evaluate the anti-inflammatory potential of repurposed drugs.
• To validate Thioridazinehydrochloride (TDZ) as an inhibitor of NF-kB activation.

Main Methods:

• Utilized a computer-aided drug identification protocol on a database of over 1500 FDA-approved drugs.
• Performed molecular docking to assess binding affinity and inhibitory potential of candidate compounds against IKKβ.
• Experimentally validated the efficacy of selected drug (TDZ) in inhibiting IκBα degradation and NF-kB activation.

Main Results:

• Identified Thioridazinehydrochloride (TDZ), an antipsychotic, as a potent inhibitor of IKKβ.
• TDZ demonstrated significant inhibition of IκBα protein degradation.
• TDZ effectively blocked NF-kB activation, thereby suppressing inflammation.

Conclusions:

• Thioridazinehydrochloride (TDZ) is a potential repurposed drug for treating inflammatory conditions.
• TDZ exerts its anti-inflammatory effects by inhibiting the IκBα/NF-kB signaling pathway.
• This study highlights the utility of drug repurposing for novel anti-inflammatory therapies.