Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

Research output: Contribution to journalArticle

Mirza S. Baig, Anjali Roy, Uzma Saqib, Sajjan Rajpoot, Mansi Srivastava, Adnan Naim, Dongfang Liu, Rohit Saluja, Syed M. Faisal, Qiuwei Pan, Kati Turkowski, Gajanan N. Darwhekar, Rajkumar Savai

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.

Original languageEnglish (US)
Article number12471
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

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Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. / Baig, Mirza S.; Roy, Anjali; Saqib, Uzma; Rajpoot, Sajjan; Srivastava, Mansi; Naim, Adnan; Liu, Dongfang; Saluja, Rohit; Faisal, Syed M.; Pan, Qiuwei; Turkowski, Kati; Darwhekar, Gajanan N.; Savai, Rajkumar.

In: Scientific Reports, Vol. 8, No. 1, 12471, 01.12.2018.

Research output: Contribution to journalArticle

Harvard

Baig, MS, Roy, A, Saqib, U, Rajpoot, S, Srivastava, M, Naim, A, Liu, D, Saluja, R, Faisal, SM, Pan, Q, Turkowski, K, Darwhekar, GN & Savai, R 2018, 'Repurposing Thioridazine (TDZ) as an anti-inflammatory agent' Scientific Reports, vol. 8, no. 1, 12471. DOI: 10.1038/s41598-018-30763-5

APA

Baig, M. S., Roy, A., Saqib, U., Rajpoot, S., Srivastava, M., Naim, A., ... Savai, R. (2018). Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. Scientific Reports, 8(1), [12471]. DOI: 10.1038/s41598-018-30763-5

Vancouver

Baig MS, Roy A, Saqib U, Rajpoot S, Srivastava M, Naim A et al. Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. Scientific Reports. 2018 Dec 1;8(1). 12471. Available from, DOI: 10.1038/s41598-018-30763-5

Author

Baig, Mirza S. ; Roy, Anjali ; Saqib, Uzma ; Rajpoot, Sajjan ; Srivastava, Mansi ; Naim, Adnan ; Liu, Dongfang ; Saluja, Rohit ; Faisal, Syed M. ; Pan, Qiuwei ; Turkowski, Kati ; Darwhekar, Gajanan N. ; Savai, Rajkumar. / Repurposing Thioridazine (TDZ) as an anti-inflammatory agent. In: Scientific Reports. 2018 ; Vol. 8, No. 1.

BibTeX

@article{a1dad2de646e4775811630958240f5a3,
title = "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-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.",
author = "Baig, {Mirza S.} and Anjali Roy and Uzma Saqib and Sajjan Rajpoot and Mansi Srivastava and Adnan Naim and Dongfang Liu and Rohit Saluja and Faisal, {Syed M.} and Qiuwei Pan and Kati Turkowski and Darwhekar, {Gajanan N.} and Rajkumar Savai",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41598-018-30763-5",
language = "English (US)",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",

}

RIS

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T1 - Repurposing Thioridazine (TDZ) as an anti-inflammatory agent

AU - Baig,Mirza S.

AU - Roy,Anjali

AU - Saqib,Uzma

AU - Rajpoot,Sajjan

AU - Srivastava,Mansi

AU - Naim,Adnan

AU - Liu,Dongfang

AU - Saluja,Rohit

AU - Faisal,Syed M.

AU - Pan,Qiuwei

AU - Turkowski,Kati

AU - Darwhekar,Gajanan N.

AU - Savai,Rajkumar

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41598-018-30763-5

DO - 10.1038/s41598-018-30763-5

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ER -

ID: 40374045