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Identification and characterization of novel ligase I inhibitors
Monica Pandey1, Sujeet Kumar2, Gunaseelan Goldsmith3
1Department of Biochemistry, Indian Institute of Science, Bangalore, India.
Abstract:
The terminal step of ligation of single and/or double-strand breaks during physiological processes such as DNA replication, repair and recombination requires participation of DNA ligases in all mammals. DNA Ligase I has been well characterised to play vital roles during these processes. Considering the indispensable role of DNA Ligase I, a therapeutic strategy to impede proliferation of cancer cells is by using specific small molecule inhibitors against it. In the present study, we have designed and chemically synthesised putative DNA Ligase I inhibitors. Based on various biochemical and biophysical screening approaches, we identify two prospective DNA Ligase I inhibitors, SCR17 and SCR21. Both the inhibitors blocked ligation of nicks on DNA in a concentration-dependent manner, when catalysed by cell-free extracts or purified Ligase I. Docking studies in conjunction with biolayer interferometry and gel shift assays revealed that both SCR17 and SCR21 can bind to Ligase I, particularly to the DNA Binding Domain of Ligase I with KD values in nanomolar range. The inhibitors did not show significant affinity towards DNA Ligase III and DNA Ligase IV. Further, addition of Ligase I could restore the joining, when the inhibitors were treated with testicular cell-free extracts. Ex vivo studies using multiple assays showed that even though cell death was limited in the presence of inhibitors in cancer cells, their proliferation was compromised. Hence, we identify two promising DNA Ligase I inhibitors, which can be used in biochemical and cellular assays, and could be further modified and optimised to target cancer cells. © 2016 Wiley Periodicals, Inc.
Insights
Researchers developed novel small molecule inhibitors, SCR17 and SCR21, targeting DNA Ligase I. These compounds effectively inhibit DNA ligation and cancer cell proliferation, offering a promising therapeutic strategy for cancer treatment.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Therapeutics
Background:
- DNA ligases are essential enzymes for DNA replication, repair, and recombination in mammals.
- DNA Ligase I plays a critical role in these fundamental cellular processes.
- Targeting DNA Ligase I with small molecule inhibitors presents a potential strategy to impede cancer cell proliferation.
Purpose of the Study:
- To design and synthesize novel small molecule inhibitors against DNA Ligase I.
- To evaluate the efficacy of these inhibitors in blocking DNA ligation and impacting cancer cell growth.
- To characterize the binding affinity and specificity of the identified inhibitors.
Main Methods:
- Chemical synthesis of putative DNA Ligase I inhibitors.
- Biochemical and biophysical screening assays (e.g., gel shift, biolayer interferometry).
- In silico molecular docking studies.
- Ex vivo studies using cancer cell lines.
Main Results:
- Two prospective DNA Ligase I inhibitors, SCR17 and SCR21, were identified.
- Both inhibitors demonstrated concentration-dependent inhibition of DNA nick ligation.
- SCR17 and SCR21 bind specifically to DNA Ligase I with nanomolar affinity, showing minimal affinity for Ligase III and IV.
- Inhibitors compromised cancer cell proliferation with limited impact on cell death.
Conclusions:
- SCR17 and SCR21 are promising DNA Ligase I inhibitors with potential for cancer therapy.
- These inhibitors can be utilized in biochemical and cellular assays.
- Further optimization of these compounds may lead to targeted cancer treatments.
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