Title:Computational and Functional Analysis of the Androgen Receptor Antagonist Atraric Acid and Its Derivatives
Volume: 13
Issue: 5
Author(s): Maria Papaioannou, Annu A. Soderholm, Wei Hong, Yifan Dai, Julia Roediger, Daniela Roell, Marie Thiele, Tommi H. Nyronen and Aria Baniahmad
Affiliation:
Keywords:
Androgen receptor, antihormone, antitumor agents, ligand binding pocket, molecular modeling, natural compound of Pygeum
africanum.
Abstract: Androgen receptor (AR) antagonists are important compounds for the treatment of prostate cancer (PCa). The atraric acid
(AA), a natural compound, binds to the AR and acts as a specific AR antagonist. Interestingly, AA represents a novel chemical platform
that could serve as a potential basis for new AR antagonists. Therefore, one objective of this study was to analyze the chemical/structural
requirements for AR antagonism and to obtain predictions of where and how AA binds to the AR. Further, this study describes the
chemical synthesis of 12 AA derivatives and their analysis using a combination of computational and functional assays. Functional
analysis of AA derivatives indicated that none activated the AR. Both the para-hydroxyl group and the benzene ortho- and the metamethyl
groups of AA appeared to be essential to antagonize androgen-activated AR activity. Furthermore, extension of the hydrophobic
side chain of AA led to slightly stronger AR antagonism. In silico data suggest that modifications to the basic AA structure change the
hydrogen-bonding network with the AR ligand binding domain (LBD), so that the para-hydroxyl group of AA forms a hydrogen bond
with the LBD, confirming the functional importance of this group for AR antagonism. Moreover, in silico modeling also suggested that
the ortho- and meta- methyl groups of AA interact with hydrophobic residues of the ligand pocket of AR, which might explain their
functional importance for antagonism. Thus, these studies identify the chemical groups of AA that play key roles in allowing the AAbased
chemical platform to act as an AR antagonist.