Computational Search for Novel Antagonists to the Metastatic Mutant Forms of the Androgen Receptor
Abstract
Prostate cancer is the most common cancer in the United States and is the second leading cause of cancer death among men in most western countries. The activation of the androgen receptor is a major factor contributing to progression of the prostate cancer. Therefore, the administration of anti-androgen (androgen antagonists) is a vital part of currently used therapies. However, limited numbers of available anti-androgens, especially those against mutant forms of androgen receptors found in metastatic prostate cancer, affect the successful outcome of a treatment. The major factor impeding discovery of novel anti-androgens was the absence of a crystal structure of the androgen receptor in antagonist conformation. Thus, the first and most important stage of the project involved development and biological validation of the model of interaction of the wild type androgen receptor with known antagonists. This model was developed, and at first validated, in silico by demonstrating docking selectivity toward known ligands. Then, an extensive ligand database was docked to the model, and the best predicted 16 binders were tested for antagonist properties using transactivation assays in CV1 cells, and their binding to the androgen receptor was confirmed by competitive binding assays. From those 16 compounds, one has shown antagonist activity comparable to that of flutamide, a clinically used antagonist. The metastatic mutants of the androgen receptor are now being modeled, based on validated models of the wild type receptor.
Document Details
- Document Type
- Technical Report
- Publication Date
- Feb 01, 2005
- Accession Number
- ADA434021
Entities
People
- Anton V. Cheltsov
Organizations
- Scripps Research