Anwar, S.Shamsi, A.Shahbaaz, M.Queen, A.Khan, P.Hasan, G.M.Islam, A.Alajmi, M.F.Hussain, A.Ahmad, F.Hassan, M.I.2023-04-172023-04-172020-06-25Anwar S, Shamsi A, Shahbaaz M, et al. Rosmarinic acid exhibits anticancer effects via MARK4 inhibition. Sci Rep 10, 10300 (2020).PMC7316822https://doi.org/10.1038/s41598-020-65648-zhttps://www.nature.com/articles/s41598-020-65648-zhttps://infospace.mrc.ac.za/handle/11288/595301Microtubule affinity regulating kinase (MARK4) is a potential drug target for different types of cancer as it controls the early step of cell division.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.enAttribution 3.0 United Stateshttp://creativecommons.org/licenses/by/3.0/us/AnticancerDrug effectsRosmarinic acidMARK4 proteinArticleScientific Reports