SBS 3.1, a novel natural product small molecule regulates TNF-α-induced NF-κB activation and key signals of inflammation to promote apoptosis in lung cancer tumour microenvironment

Abstract

Chronic inflammation leads to many maladies in lung cancer. Tumor necrosis factor-alpha (T NF- α), a pleiotropic proinflammatory cytokine regulates the activation of the nuclear factor-κB (NF-κB) to drive many physiological and pathological signaling pathways in inflammation and cancer apoptosis. This study identified a novel natural product to inhibit T NF-α induced NF-κB activation. Virtual docking of ZINC natural product library and computational modeling analysis showed compounds that target crucial amino acid residues on p50 protein involved in DNA binding. Molecular dynamic simulation showed, compound SBS-3.1, as the best lead compound that binds efficiently and stably with p50 protein. MMP BSA analysis of the lead compound predicted a favorable binding free energy. The compound inhibited the proliferations of T NF-α induced A-549 with a GI50 value of 30.53 μM. SBS-3.1 decreased the percentage of T NF-α induced NF-κB-65, p38 and ERK1/2 positive lung cancer cells, while the apoptosis in these cells were elevated. In summary, SBS-3.1, a natural product, was identified as the lead compound targeting Rel-homology region of p50. Inhibition of NF-κB and inflammatory signals by SBS 3.1 promoted apoptosis in lung cancer. Further research can bring new therapeutic strategies for treating inflammation associated T ME of lung cancer cells.

Communicated by Ramaswamy H. Sarma

Keywords:

• High-throughput virtual screening
• Rel-homology region
• MD simulation
• GROMACS
• MMPBSA
• NF-κB
• P38 and ERK1/2

Acknowledgments

Authors express their gratitude to SMARTBIO LABS, Chennai-78, Tamil Nadu, India, and SiBI-OLEAD, Little Rock, Arkansas, USA, for the help rendered in this study.

Authors’ contributions

A Kumar—Study design, literature survey, experimental, data curing, manuscript and communication.

Disclosure statement

The author of this manuscript declares there in no any conflict of interest related to the study.

Data availability statement

The data used in manuscript is available with corresponding author for non-commercial purposes.

Additional information

Funding

The author extends his appreciation to the Deanship of Scientific Research at King Khalid University for funding this work through large group Research Project under grant number RGP2/147/44.