Abstract
DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. In this work, we employed a High Throughput Virtual screening approach to identify bioactive compounds against DDX3 from ZINC natural database. Ketorolac salt was selected based on its binding free energy less than or equals to −5 Kcal/mol with reference to existing synthetic DDX3 inhibitors and strong hydrogen bond interactions as similar to crystallized DDX3 protein (2I4I). The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 µM. Ketorolac salt also inhibited the ATP hydrolysis by directly interacting with DDX3. More importantly, we observed decreased number of neoplastic tongue lesions and reduced lesion severity in Ketorolac salt treated groups in a carcinogen induced tongue tumor mouse model. Taken together, our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer.
Highlights
DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer
Our result demonstrates that Ketorolac salt is a newly discovered bioactive compound against DDX3 and this compound can be used as an ideal drug candidate to treat DDX3 associated oral cancer
To identify the bioactive compounds against DDX3, a set of 1, 22,163 commercially available bioactive molecules were collected from a ZINC database, and they were passed through FILTER 2.0.2 to remove undesirable non-lead like compounds using the default filter lead parameter file (OpenEye Scientific Software v. 2.0.2)
Summary
DDX3 belongs to DEAD box RNA helicase family and is involved in the progression of several types of cancer. The anti-cancer activity of Ketorolac salt against DDX3 was tested using oral squamous cell carcinoma (OSCC) cell lines. This compound significantly down regulated the expression of DDX3 in human OSCC line (H357) and the half maximal growth inhibitory concentration (IC50) of Ketorolac salt in H357 cell line is 2.6 mM. R NA helicases are distinct family members found in all eukaryotes and in majority of prokaryotes[1,2] These members are distinguished from others based on conserved amino-acid sequence Asp-Glu-Ala-Asp/His (DEAD/H)[3,4].
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