Novel Butein Derivatives Repress DDX3 Expression by Inhibiting PI3K/AKT Signaling Pathway in MCF-7 and MDA-MB-231 Cell Lines

Abstract

BackgroundBreast cancer is one of the major causes of mortalities noticed in women globally. DDX3 has emerged as a potent target for several cancers, including breast cancer to which currently there are no reported or approved drugs.MethodsTo find effective cancer therapeutics, three compounds were computationally designed tweaking the structure of natural compound butein. These compounds were synthesized and evaluated for their anticancer property in MCF-7 and MDA-MB-231 cell lines targeting DDX3. The in silico molecular docking studies have shown that the compounds have occupied the binding site of the human DDX3 target. Furthermore, to investigate the cell viability effect of 3a, 3b, and 3c on MCF-7 and MDA-MB-231 cell lines, the cell lines were treated with different concentrations of compounds for 24 and 48 h and measured using MTT assay.ResultsThe cell viability results showed that the have induced dose dependent suppression of DDX3 expression. Additionally, 3b and 3c have reduced the expression of DDX3 in MCF-7 and MDA-MD-231 cell lines. 3b or 3c treated cell lines increased apoptotic protein expression. Both the compounds have induced the apoptotic cell death by elevated levels of cleaved PARP and cleaved caspase 3 and repression of the anti-apoptosis protein BCL-xL. Additionally, they have demonstrated the G2/M phase cell cycle arrest in both the cell lines. Additionally, 3c decreased PI3K and AKT levels.ConclusionsOur results shed light on the anticancer ability of the designed compounds. These compounds can be employed as chemical spaces to design new prospective drug candidates. Additionally, our computational method can be adapted to design new chemical scaffolds as plausible inhibitors.

Explicit molecular dynamics simulation studies to discover novel natural compound analogues as Mycobacterium tuberculosis inhibitors

“…Six compounds were used against the validated target Mt DTBS. Out of the six compounds, two compounds are novel and have shown anticancer activity in our previous study [ 7 ]. The target structure chosen for the current study is complexed with adenosine-5′-diphosphate and Mg ion.…”

“…The six small molecules used for the current study are available in the lab. The three compounds are earlier published from our group [ 7 ]. These small molecules were prepared by using the ‘ full minimization ’ module available with the DS.…”

“…To elucidate the predictive binding mode and to assess the binding affinity of the selected compounds towards the Mycobacterium tuberculosis , the CDOCKER available with the discovery studio v18 (DS) was used. In the current study six compounds, three from the previous study were also included [ 7 ]. The CDOCKER docking method used here is a grid-based molecular docking method that uses CHARMm.…”

“…In the current study, for discovering the potential inhibitors against Mt DTBS, we have used various in silico methods such as molecular docking, molecular dynamics simulation (MDS) and essential dynamics. These studies have proven to be crucial in swiftly identifying the plausible inhibitors [ [6] , [7] , [8] , [9] , [10] , [11] , [12] ]. Particularly, a few studies report the use of in silco methods in identifying potential inhibitors for Mt .…”

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“…Antihyperglycemic, antinociceptive effect, antiperoxidative, and hypoglycemic effects PI3K/AKT Signaling pathway in cancer lines. [41] It also suppresses expression of nuclear factor-kappa β-mediated matrix metalloproteinase-9 and vascular endothelial growth factor in prostate cancer cells. [42] It induces apoptosis in MCF-7 breast cancer cells through cell cycle arrest.…”