Rosmarinic Acid Exhibits Anticancer Effects via MARK4 Inhibition
Saleha Anwar, Anas Shamsi, Mohd Shahbaaz, Aarfa Queen, Parvez Khan, Gulam Mustafa Hasan, Asimul Islam, Mohamed F. Alajmi, Afzal Hussain, Faizan Ahmad, Md. Imtaiyaz Hassan
Microtubule affinity regulating kinase (MARK4) is a potential drug target for different types of cancer as it controls the early step of cell division. In this study, we have screened a series of natural compounds and finally identified rosmarinic acid (RA) as a potential inhibitor of MARK4. Molecular docking and 500 ns all-atom simulation studies suggested that RA binds to the active site pocket of MARK4, forming enough number of non-covalent interactions with critical residues and MARK4-RA complex is stable throughout the simulation trajectory. RA shows an excellent binding affinity to the MARK4 with a binding constant (K) of 107 M−1. Furthermore, RA significantly inhibits MARK4 activity (IC50 = 6.204 µM). The evaluation of enthalpy change (∆H) and entropy change (∆S) suggested that the MARK4-RA complex formation is driven by hydrogen bonding and thus complexation process is seemingly specific. The consequence of MARK4 inhibition by RA was further evaluated by cell-based tau-phosphorylation studies, which suggested that RA inhibited the phosphorylation of tau. The treatment of cancer cells with RA significantly controls cell growth and subsequently induces apoptosis. Our study provides a rationale for the therapeutic evaluation of RA and RA-based inhibitors in MARK4 associated cancers and other diseases.
Fluorescence, Quenching, Ligand binding, Thermal stability, Protein structure, Biochemistry