REVOLUTIONIZING CANCER THERAPY: REPURPOSING FDA- APPROVED DRUGS FOR ERK1(MAPK3) INHIBITION VIA INTEGRATED DOCKING AND SIMULATION STRATEGY

Abstract

Cancer , a common disease worldwide, defined by the aberrant cells' uncontrollable growth and division, resulting in the development of tumors, which may be harmless, dangerous, or both. Tumors that are cancerous have the ability to infect nearby tissues and spread across other body areas. The rapid growth and dissemination of these aberrant cells are the primary causes of cancer-related deaths Worldwide, cancer is a common disease, and DNA damage is frequently the source of sporadic tumors. A significant contributing element to the onset and spread of cancer because of many genes showing expression which are altered, including kinases. The growth of cancer may be aided by several cellular abnormalities brought on by this abnormal expression. The serine/threonine kinase ERK1(MAPK3) is a member of the MAP kinase family. Because it is an essential part of the ERK/MAPK signaling cascade, ERK1 regulates a number of cellular processes that are disturbed in cancer pathogenesis. When dysregulated, it leads to uncontrollable cell growth because it activates transcription factors that govern gene expression relevant to the progression of the cell cycle, promoting cell proliferation. Numerous malignancies, including those of the liver, pancreas, breast, thyroid, and other organs, are associated with poor prognoses, resistance to therapy, spread, and initiation that are all linked to ERK1 (MAPK3). Thus, it appears that ERK1 (MAPK3) is a viable target for treatment. In order to determine possible ERK1 inhibitors ERK1, a comprehensive strategy was employed. This included docking simulations on 3,674 FDA-approved drugs to find compounds with higher affinity than existing medications. A detailed screening process narrowed down the candidates. Interaction analysis was then performed on 14 ligands with higher binding affinity than the reference drug. Swiss ADME analysis assessed the physiochemical properties, bioavailability, gastrointestinal absorption, solubility, and Ames toxicity of the selected ligands. Furthermore, the biological function of the resulting compounds was anticipated by PASS analysis. To further understand the stability and dynamic behaviour of these compounds within the ERK1 binding region, a 100 ns MDS was performed, providing insights into the structural dynamics and stability of the compound-ERK1 complex. Among the analysed drugs, one compound stood out as a promising ERK1 inhibitor. The selection process considered not only binding affinity but also essential v physiochemical properties, toxicity analysis, pharmacokinetic properties, stability, and conformational dynamics. This thorough methodology, integrating molecular docking with a vast library of FDA-approved drugs, advanced interaction analysis, ADME and PASS analysis, and finally MD simulation for studying dynamic and stability behaviour, significantly increases the chances of identifying a viable therapeutic candidate. Such an integrated approach shows great promise in identifying novel ERK1 (MAPK3) inhibitors, laying a solid foundation for subsequent preclinical and clinical studies.