Rosmarinic Acid Exhibits Anticancer Effects via MARK4 Inhibition.

ABSTRACT: 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.

SUBMITTER: Anwar S 

PROVIDER: S-EPMC7316822 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature