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image of In silico Prediction of Pranlukast as a Stabilizer of PD-L1 Homodimers

Abstract

Introduction

Tumors can be targeted by modulating the immune response of the patient. Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are critical immune checkpoints in cancer biology. The efficacy of certain cancer immunotherapies has been achieved by targeting these molecules using monoclonal antibodies.

Method

Small-molecule drugs have also been developed as inhibitors of the PD-1/PD-L1 axis, with a mechanism of action that is distinct from that of antibodies: they induce the formation of PD-L1 homodimers, causing their stabilization, internalization, and subsequent degradation. Drug repurposing is a strategy in which new uses are sought after for approved drugs, expediting their clinical translation based on updated findings. In this study, we generated a pharmacophore model that was based on reported small molecules that targeted PD-L1 and used it to identify potential PD-L1 inhibitors among FDA-approved drugs.

Results

We identified 12 pharmacophore-matching compounds, but only 4 reproduced the binding mode of the reference inhibitors in docking experiments. Further characterization by molecular dynamics showed that pranlukast, an antagonist of leukotriene receptors that is used to treat asthma, generated stable and energy-favorable interactions with PD-L1 homodimers and induced homodimerization of recombinant PD-L1.

Conclusion

Our results suggest that pranlukast inhibits the PD-1/PD-L1 axis, meriting its repurposing as an antitumor drug.

© 2024 Bentham Science Publishers
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2024-10-17
2024-12-04

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/content/journals/acamc/10.2174/0118715206303675241009104647
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In silico Prediction of Pranlukast as a Stabilizer of PD-L1 Homodimers
Bentham Science Publishers ; https://doi.org/10.2174/0118715206303675241009104647
/content/journals/acamc/10.2174/0118715206303675241009104647
/content/journals/acamc/10.2174/0118715206303675241009104647
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  • Article Type:     Research Article
Keywords: pranlukast ; pharmacophore modeling ; virtual screening ; drug repurposing ; Immune checkpoint ; molecular dynamics

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