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Theoretical Studies of Anti-cancer Drug Tamoxifen and Estrogen Receptor Alpha
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
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: urn:nbn:se:kth:diva-105721ISBN: 978-91-7501-586-6 (print)OAI: oai:DiVA.org:kth-105721DiVA: diva2:571758
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
List of papers
1. More stable, more estrogenic: the SERM-ERα LBD complex
Open this publication in new window or tab >>More stable, more estrogenic: the SERM-ERα LBD complex
2011 (English)In: Journal of Biophysical Chemistry, ISSN 2153-036X, E-ISSN 2153-0378, Vol. 2, no 3, 233-243 p.Article in journal (Refereed) Published
Abstract [en]

Many synthetic selective estrogen receptor mo- dulators (SERMs) have been cocrystallized with the human estrogen receptor α ligand binding domain (ERα LBD). Despite stabilizing the same canonical inactive conformation of the LBD, most SERMs display different ligand-dependent pharmacological profiles. We show here that in-creased partial agonism of SERMs is associated with increased conformational stability of the SERM-LBD complexes, by investigation of dihy-drobenzoxathiin-based SERMs using molecular modelling techniques. Analyses of tamoxifen (TAM) and 4-hydroxytamoxifen (OHT) in complex with the LBD furthermore indicates that the conversion of TAM to OHT increases both the affinity to ERα and the partial agonism of the anti-cancer drug, which provides a plausible ex-planation of the counterintuitive results of TAM therapy.

Keyword
Breast Cancer; Tamoxifen Resistance; Molecular Dynamics Simulations; Dihydrobenzoxathiin; SERM
National Category
Natural Sciences
Identifiers
urn:nbn:se:kth:diva-78518 (URN)10.4236/jbpc.2011.23029 (DOI)
Note

20120208

Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08Bibliographically approved
2. Conformational Enantiomerization and Estrogen Receptor alpha Binding of Anti-Cancer Drug Tamoxifen and Its Derivatives
Open this publication in new window or tab >>Conformational Enantiomerization and Estrogen Receptor alpha Binding of Anti-Cancer Drug Tamoxifen and Its Derivatives
Show others...
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.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-105742 (URN)10.1021/ci100401t (DOI)000287685700012 ()
Funder
Swedish Research Council
Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2012-11-26Bibliographically approved
3. A Mechanistic Hypothesis for the Cytochrome P450-Catalyzed Cis-Trans Isomerization of 4-Hydroxytamoxifen: An Unusual Redox Reaction
Open this publication in new window or tab >>A Mechanistic Hypothesis for the Cytochrome P450-Catalyzed Cis-Trans Isomerization of 4-Hydroxytamoxifen: An Unusual Redox Reaction
Show others...
2011 (English)In: Journal of chemical information and modeling, ISSN 1549-9596, Vol. 51, no 9, 2293-2301 p.Article in journal (Refereed) Published
Abstract [en]

We provide a detailed description of the cis-trans isomerization of 4-hydroxytamoxifen/endoxifen catalyzed by several isoforms from the cytochrome P450 (CYP) superfamily, including CYP1B1, CYP2B6, and CYP2C19. We show that the reactions mainly involve redox processes catalyzed by CYP, DFT calculation results strongly suggest that the isomerization occurs via a cationic intermediate. The cationic cis-isomer is more than 3 kcal/mol more stable than the trans form, resulting in an easier conversion from trans-to-cis than cis-to-trans. The cis-trans isomerization is a rarely reported CYP reaction and is ascribed to the lack of a second abstractable proton on the ethenyl group of the triarylvinyl class of substrates. The cationic intermediates thus formed instead of the stable dehydrogenation products allow for isomerization to occur. As a comparison, the reactions for the tamoxifen derivatives are compared to those of other substrates, 4-hydroxyacetanilide and raloxifene, for which the stable dehydrogenation products are formed.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:kth:diva-105743 (URN)10.1021/ci2001082 (DOI)000295114700026 ()2-s2.0-80053302488 (Scopus ID)
Note

QC 20121126

Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2012-11-26Bibliographically approved
4. Modification of the anticancerdrug tamoxifen to avoid CYP2D6 polymorphism
Open this publication in new window or tab >>Modification of the anticancerdrug tamoxifen to avoid CYP2D6 polymorphism
(English)Manuscript (preprint) (Other academic)
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-105744 (URN)
Note

QS 2012

Available from: 2012-11-26 Created: 2012-11-26 Last updated: 2012-11-26Bibliographically approved
5. Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain
Open this publication in new window or tab >>Characterization of Agonist Binding to His524 in the Estrogen Receptor alpha Ligand Binding Domain
2012 (English)In: Journal of Physical Chemistry B, ISSN 1520-6106, E-ISSN 1520-5207, Vol. 116, no 16, 4823-4830 p.Article in journal (Refereed) Published
Abstract [en]

The bioactivities of the natural steroidal estrogen 17 beta-estradiol (E-2), the synthetic estrogen diethylstilbestrol (DES), and the phytoestrogen genistein (GEN) are intimately associated with their binding to the estrogen receptor alpha ligand binding domain (ER alpha LBD) and accordingly allostery. Molecular modeling techniques have been performed on agonists in complex with the LBD, focusing on the pivotal role of His524 modeled as the epsilon-tautomer and the protonated form (depending on pH). It is found that E-2 binds to the active LBD with the aid of Leu525, showing existing stable patterns of an H-binding network with Glu419 via His524 in all models. The main difference seen in the effect is that the full agonists E-2 and DES have higher binding energies to the protonated His524 than the partial agonists GEN and Way-169916 (W), which is in line with noted experimental transcriptional activities. In conclusion, the study demonstrates that the phytoestrogen GEN interacts differently with the LBD than what E-2 and DES do, which explains the observed signaling differences.

Keyword
Allostery, Estrogen receptor, Genistein, H-binding, In-line, Ligand binding domain, Molecular modeling techniques, Phytoestrogenes, Protonated, Stable patterns, Steroidal estrogens, Transcriptional activity
National Category
Physical Chemistry
Identifiers
urn:nbn:se:kth:diva-95251 (URN)10.1021/jp300895g (DOI)000303173800011 ()22482773 (PubMedID)2-s2.0-84860290278 (Scopus ID)
Funder
Swedish Research CouncilSwedish e‐Science Research Center
Note

QC 20120521

Available from: 2012-05-21 Created: 2012-05-21 Last updated: 2017-12-07Bibliographically approved

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