Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha

Abstract: For decades tamoxifen (TAM) has been widely used for treatment of breast cancer by mediating mainly the estrogen receptor α (ERα) signaling pathways, whereby it suppresses estrogen stimulated cancer cell growth. The clinical response of TAM has been linked to cytochrome P450 2D6 (CYP2D6), which is the main isoform responsible for the conversion of TAM to the active metabolites 4-hydroxyTAM (OHT) and endoxifen. Numerous clinical studies have thus attempted to assess the effects of CYP2D6 genetic variants on patients treated by TAM. However, the studies have resulted in contradictive conclusions. This thesis focuses on computational investigations of TAM and its main target ERα. The results obtained describe how the ligands contact with the ERα ligand binding domain (LBD), and provide possible mechanisms responsible for the CYP2D6 activating in TAM treatment. In addition, the CYP-mediated biotransformation of TAM-like compounds is investigated. All studies in this thesis aim to a step towards developing improved therapeutic agents for breast cancer treatment. In paper I, molecular dynamics simulations of ligand-LBD complexes have been performed. The results indicate that although OHT is a high affinity metabolite, it may have more undesired estrogen-like properties than the parent drug TAM, as a consequence of the additional 4-hydroxy group. In papers II and V, quantum mechanics calculations have been performed to study how the ligands are bound to ERα LBD. It is found that different conformational isomers of TAM-like ligands are discriminated by the LBD. The interactions between ligands and His524-Leu525 in the LBD are correlated with the transcriptional activity of estrogen agonist compounds. In papers III and IV, different CYP-mediated biotransformations of TAM and derivatives are studied. Based on the results from the computations, we suggest two modified compounds which are highly possible to be activated by other CYP isoforms besides CYP2D6, thereby avoiding CYP2D6 genetic polymorphism. Overall, the results generally agree with the hitherto available experimental results. Further experimental studies are needed to verify the proposed principles of ligands signaling through ERα, and to test the suggested CYP-mediated reactions and the bioactivity of the modified compounds.