Repurposing Statins as MAPK Pathway Inhibitors: Docking and Molecular Dynamics Insights into Cancer Therapeutics

Abstract

The Mitogen Activated Protein Kinase (MAPK) pathway, comprising KRAS, BRAF, MEK, and ERK, regulates cell proliferation, differentiation, and survival. Dysregulated MAPK signaling drives tumor growth in ovarian, colorectal, lung, and breast cancers, making it a critical target for therapy. Statins, widely prescribed HMG CoA reductase inhibitors, block the mevalonate pathway and prevent RAS prenylation, indirectly suppressing MAPK activation. This connection highlights statins as promising candidates for drug repurposing in oncology. Seven FDA approved statins, Atorvastatin, Simvastatin, Lovastatin, Rosuvastatin, Pravastatin, Fluvastatin, and Pitavastatin, were evaluated against key MAPK proteins. Protein structures of KRAS (6OIM), BRAF (4WO5), MEK1 (3EQG), and ERK2 (4QTB) were retrieved from the RCSB PDB database. Molecular docking assessed binding affinities and interactions, identifying five statins with the most favorable profiles. Four lead protein statin complexes were further analyzed using all atom molecular dynamics simulations in GROMACS with the CHARMM36 force field. Stability and dynamics were examined via Root Mean Square Deviation, Root Mean Square Fluctuation, Solvent Accessible Surface Area, hydrogen bonding, and clustering analyses. Docking revealed strong binding of multiple statins to MAPK proteins, while molecular dynamics confirmed stable interactions at the atomic level. These results underscore statins as effective MAPK modulators and provide structural insights supporting their repurposing for cancer therapy. Integrating docking with all atom molecular dynamics establishes a rational strategy to prioritize statins for preclinical evaluation, highlighting their potential as safe, accessible, and effective anticancer agents.