Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
More stable, more estrogenic: the SERM-ERα LBD complex
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.
KTH, School of Biotechnology (BIO), Theoretical Chemistry and Biology.ORCID iD: 0000-0001-8198-9284
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.

Place, publisher, year, edition, pages
2011. Vol. 2, no 3, 233-243 p.
Keyword [en]
Breast Cancer; Tamoxifen Resistance; Molecular Dynamics Simulations; Dihydrobenzoxathiin; SERM
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:kth:diva-78518DOI: 10.4236/jbpc.2011.23029OAI: oai:DiVA.org:kth-78518DiVA: diva2:492578
Note

20120208

Available from: 2012-02-08 Created: 2012-02-08 Last updated: 2017-12-08Bibliographically 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

Open Access in DiVA

No full text

Other links

Publisher's full text

Authority records BETA

Tu, Yaoquan

Search in DiVA

By author/editor
Gao, LiTu, Yaoquan
By organisation
Theoretical Chemistry and Biology
In the same journal
Journal of Biophysical Chemistry
Natural Sciences

Search outside of DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetric score

doi
urn-nbn
Total: 106 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf