Abstract
Microtubule affinity regulating kinase 4 (MARK4) is a Ser/Thr kinase belonging to AMPK-like family, has recently become an important drug target against cancer and neurodegenerative disorders. In this study, we have evaluated different natural dietary polyphenolics including rutin, quercetin, ferulic acid, hesperidin, gallic acid and vanillin as MARK4 inhibitors. All compounds are primarily binds to the active site cavity of MARK4. In silico observations were further complemented by the fluorescence-binding studies and isothermal titration calorimetry (ITC) measurements. We found that rutin and vanillin bind to MARK4 with a reasonably high affinity. ATPase and tau-phosphorylation assay further suggesting that rutin and vanillin inhibit the enzyme activity of MARK4 to a great extent. Cell proliferation, ROS quantification and Annexin-V staining studies are clearly providing sufficient evidences for the apoptotic potential of rutin and vanillin. In conclusion, rutin and vanillin may be considered as potential inhibitors for MARK4 and further exploited to design novel therapeutic molecules against MARK4 associated diseases.
Highlights
From the ancient time natural compounds or phytonutrients are known for their potential therapeutic applications and almost 60% of the drugs used in treating cancer are basically plant-derived compounds[20]
Polyphenols are known for their anticancer, antidiabetic and antiproliferative ability were used for docking with Microtubule affinity regulating kinase 4 (MARK4) to see possible interactions
Natural dietary polyphenolic compounds have been established as significant anticancer and neuroprotective therapeutic agents due to their potential of tumor growth inhibition, angiogenesis, metastasis, induction of apoptosis in cancer cells and neuroprotection without parting major side effects[44,45,46]
Summary
From the ancient time natural compounds or phytonutrients are known for their potential therapeutic applications and almost 60% of the drugs used in treating cancer are basically plant-derived compounds[20]. It is known that polyphenols and flavonoids decreases cell viability and induces apoptosis in many prostate and breast cancer cell lines[41, 47,48,49] These plant-based phenolic compounds target AMPK, PK-A, Akt and MAPK pathways in different organs like pancreas, muscle, liver and white adipocytes where they affect the glucose homeostasis and control diabetes[50, 51]. These therapeutic effects can’t be generalized as some studies have reported inconclusive and even harmful results[52,53,54]. These natural compounds can be considered as a potential inhibitor for MARK4
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