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Multifaceted In Silico Screening Strategies Identifies Potent Inhibitors Facilitating Inhibition of ZNF726 Activity
Shreetama Bandyopadhayaya1, Pooja Yadav1, Monika Kumari1
1Department of Biochemistry, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India.
Abstract:
Studies documented by our lab established ZNF726 to potently augment the tumorigenic behavior of breast cancer cells by increasing cellular cholesterol levels. Therefore, Zinc finger protein 726 (ZNF726) can be considered an attractive therapeutic target for the treatment of breast cancer. Based on these views, this study aimed to identify potent inhibitors targeting ZNF726 activity utilizing a structure-based molecular docking method. Virtual screening with the LOPAC library led to the identification of zoledronic acid monohydrate as a top-hit compound featuring good docking and MMGBSA scores. Further, zoledronic acid monohydrate was found to inhibit the proliferation potential of breast cancer cells. Ectopic expression of ZNF726 led to an increase in the cholesterol levels of breast cancer cells. Further, this study confirms that zoledronic acid tends to decrease the cholesterol content in ZNF726-overexpressed cells along with an inhibitory effect on breast cancer cell proliferation. Conclusively, these findings suggested that the cholesterol pathway and oncogenic ZNF726 form an interdependent relationship, and therefore, targeting the cholesterol pathway may prove to be a promising strategy to inhibit oncogenic ZNF726 expression in breast cancer. Additionally, this study also reveals nine phytochemicals that might target ZNF726 activity, identified through virtual screening by the IMPPAT library. Three phytochemicals (Swertiamacroside, Terflavin A, and N-(3-Carboxy-2,3-dihydroxypropyl)-4-((carboxymethyl)amino) threonine) out of the nine phytochemicals are still unknown for their anticancer role which needs further exploration. Briefly, this study draws attention toward finding potential therapeutics against the carcinogenic effects of ZNF726 by multiple in silico approaches.
Insights
Zinc finger protein 726 (ZNF726) drives breast cancer by increasing cholesterol. Zoledronic acid monohydrate inhibits ZNF726, reducing cancer cell proliferation and cholesterol levels, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Biochemistry
- Computational Chemistry
Background:
- Zinc finger protein 726 (ZNF726) promotes breast cancer tumorigenesis by elevating cellular cholesterol.
- ZNF726 represents a potential therapeutic target for breast cancer treatment.
Purpose of the Study:
- To identify potent inhibitors of ZNF726 activity using structure-based molecular docking.
- To explore the relationship between ZNF726, cholesterol pathways, and breast cancer progression.
Main Methods:
- Virtual screening of the LOPAC library using molecular docking and MMGBSA scoring.
- Assessing the effect of identified compounds on breast cancer cell proliferation and cholesterol levels.
- Investigating ZNF726's role in regulating cellular cholesterol content.
Main Results:
- Zoledronic acid monohydrate emerged as a top-hit inhibitor of ZNF726, demonstrating significant docking and MMGBSA scores.
- Zoledronic acid monohydrate inhibited breast cancer cell proliferation and reduced cholesterol levels in ZNF726-overexpressing cells.
- Nine phytochemicals with potential ZNF726 inhibitory activity were identified via virtual screening of the IMPPAT library.
Conclusions:
- The cholesterol pathway and oncogenic ZNF726 are interdependent in breast cancer.
- Targeting the cholesterol pathway is a promising strategy to inhibit ZNF726 in breast cancer.
- Zoledronic acid monohydrate and identified phytochemicals warrant further investigation as potential breast cancer therapeutics.
