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Conformational Enantiomerization and Estrogen Receptor alpha Binding of Anti-Cancer Drug Tamoxifen and Its Derivatives
Örebro Life Science Center, School of Science and Technology, Örebro University.
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2011 (English)In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 51, no 2, 306-314 p.Article in journal (Refereed) Published
Abstract [en]

The anticancer drug tamoxifen (TAM) displays two chiral vinyl propeller structures, which interconvert so rapidly that the process is undetectable on the NMR time scale. In the present work, the enantiomerization processes were investigated with molecular modeling techniques. The threshold mechanisms probed at the different rings were shown to be identical, i.e., involving a synchronous three-ring flip, with a correlated rotation of the rings. In order to reveal the pharmacological profiles of the two chiral forms, we performed structural studies on the ligand binding domain of estrogen receptor alpha. (ER alpha LBD) and associated ligands. The enantiomers, with opposite torsional twist, were found to be discriminated by ER alpha. For TAM and its main metabolites, the effects of the stereoselectivity of ER alpha are overcome by the low energy cost for helical inversion between the two torsional enantiomers, estimated to be similar to 3 kcal/mol.

Place, publisher, year, edition, pages
2011. Vol. 51, no 2, 306-314 p.
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:kth:diva-105742DOI: 10.1021/ci100401tISI: 000287685700012OAI: oai:DiVA.org:kth-105742DiVA: diva2:571909
Funder
Swedish Research Council
Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2012-11-26Bibliographically approved
In thesis
1. Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
Open this publication in new window or tab >>Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. vi, 58 p.
Series
Trita-BIO-Report, ISSN 1654-2312 ; 2012:23
National Category
Theoretical Chemistry
Identifiers
urn:nbn:se:kth:diva-105721 (URN)978-91-7501-586-6 (ISBN)
Public defence
2012-12-18, FB53, Albanova Universitetscentrum, Stockholm, 14:00 (English)
Opponent
Supervisors
Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-23 Last updated: 2012-11-26Bibliographically approved

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