Journal
JOURNAL OF CELLULAR BIOCHEMISTRY
Volume 123, Issue 2, Pages 359-374Publisher
WILEY
DOI: 10.1002/jcb.30176
Keywords
cancer cell lines; drug discovery; isothermal titration calorimetry; kinase inhibitor; molecular dynamics simulation
Categories
Funding
- Taif University Researchers Supporting [TURSP-2020/131]
- National Medicinal Plants Board, Ministry of AYUSH, Government of India [Z.18017/187/CSS/R&D/DL-01/2019-20-NMPB-IVA]
- Indian Council of Medical Research [45/37/2019-BIO/BMS]
- Council of Scientific and Industrial Research [27(0368)/20/EMR-II]
- National Research Foundation (NRF)
- Department of Science and Technology, Government of India [SR/FST/LSII/2020/782]
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The study identified Myricetin as a potential inhibitor of MARK4, a promising anticancer molecule, which showed significant inhibition of MARK4 and cancer cell proliferation through various experiments.
Identifying novel molecules as potential kinase inhibitors are gaining significant attention globally. The present study suggests Myricetin as a potential inhibitor of microtubule-affinity regulating kinase (MARK4), adding another molecule to the existing list of anticancer therapeutics. MARK4 regulates initial cell division steps and is a potent druggable target for various cancers. Structure-based docking with 100 ns molecular dynamics simulation depicted activity of Myricetin in the active site pocket of MARK4 and the formation of a stable complex. The fluorescence-based assay showed excellent affinity of Myricetin to MARK4 guided by static and dynamic quenching. Moreover, the assessment of enthalpy change ( increment H) and entropy change ( increment S) delineated electrostatic interactions as a dominant force in the MARK4-myricetin interaction. Isothermal titration calorimetric measurements revealed spontaneous binding of Myricetin with MARK4. Further, the kinase assay depicted significant inhibition of MARK4 by Myricetin with IC50 = 3.11 mu M. Additionally, cell proliferation studies established that Myricetin significantly inhibited the cancer cells (MCF-7 and A549) proliferation, and inducing apoptosis. This study provides a solid rationale for developing Myricetin as a promising anticancer molecule in the MARK4 mediated malignancies.
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