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Structural characterization of androgen receptor interactions with nonsteroidal ligands

Bohl, Casey Edward
http://rave.ohiolink.edu/etdc/view?acc_num=osu1116362600

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Pharmacy.
The following research was aimed at uncovering the binding interactions of nonsteroidal ligands with the androgen receptor (AR). Steroidal binding to the AR is well understood through x-ray crystallography and mutational analysis. The binding mechanism for the nonsteroidal antiandrogens used in prostate cancer treatment however was unknown despite prevalent clinical use for nearly 20 years. Our laboratory discovered selective androgen receptor modulators (SARMs) by structural modification of currently available nonsteroidal antiandrogens. Collaboration with a group of medicinal chemists led to a vast number of potential therapeutic agents that target the AR, but their binding mechanism could not be explained based on currently published crystal structures complexed to steroids. We investigated the interactions between nonsteroidal ligands and the AR using a variety of approaches including molecular modeling, mutational analysis, and x-ray crystallography. Nonsteroidal ligands induced structural changes in the AR binding pocket allowing for their accommodation. Furthermore, crystal structures of currently prescribed antiandrogens complexed to mutant AR associated with resistance provided information regarding their mechanism of action. Knowledge of AR interactions with nonsteroidal ligands will provide the basis for development of improved drugs that target the AR.
James Dalton (Advisor)
Health Sciences, Pharmacology
bicalutamide; LBD; AR LBD; AR; SARMs; DHT; LIGANDS

Recommended Citations

Citations

  • Bohl, C. E. (2005). Structural characterization of androgen receptor interactions with nonsteroidal ligands [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116362600

    APA Style (7th edition)

  • Bohl, Casey. Structural characterization of androgen receptor interactions with nonsteroidal ligands. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1116362600.

    MLA Style (8th edition)

  • Bohl, Casey. "Structural characterization of androgen receptor interactions with nonsteroidal ligands." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1116362600

    Chicago Manual of Style (17th edition)

osu1116362600
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.