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Computational Characterization of 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5b]pyridine at Androgen Receptor: Mechanistic support for its role in Prostate Cancer
Author(s) -
Glass-Holmes Mashunte,
Aguilar Byron,
Oriaku Ebenezer,
Goodman Carl B.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1038.4
Subject(s) - androgen receptor , chemistry , prostate cancer , docking (animal) , carcinogenesis , cancer research , receptor , pyridine , pharmacology , computational biology , biochemistry , cancer , medicine , biology , gene , medicinal chemistry , nursing
The cooked meat‐derived carcinogenic heterocyclic amine 2‐amino‐1‐methyl‐6‐phenylimidazo[4,5b]pyridine (PhIP) has been shown to produce tissue specific tumors in animal models. The mechanism for this specificity has not been fully elucidated and has been attributed to organ differences. In order to evaluate the modifying effects of PhIP on carcinogenesis we analyzed its ability to activate or inhibit an androgenic response. The present study seeks to evaluate the interactions of PhIP and identify molecular events associated with PhIP‐mediated disruption of the androgen receptor (AR) function. We demonstrate that PhIP binds with the ligand‐binding domain by computational analysis. Using molecular docking simulations, of ArgusLab and Molegro, we have identified a possible binding mode of PhIP to the AR based on the predicted binding free energy, compared to that of DHT at the AR. This molecular docking simulation gives insight into the molecular mechanism by which PhIP is able to initiate transduction of the activation signal. Additional studies using receptor‐binding experiments will be used to confirm modeling data. Our Docking results indicate tht PhIP may play an important role in the modification of AR gene expression and initiation of prostate cancer. Research supported by NCRR/RCMI G12 RR03020, NIGMS/MBRS/SCORE GM08111, and HRSA SD34HP0 4018.