2YHD

Human androgen receptor in complex with AF2 small molecule inhibitor

Summary for 2YHD

• Entry DOI: 10.2210/pdb2yhd/pdb
• Related: 1E3G 1GS4 1T5Z 1T63 1T65 1XJ7 1XOW 1XQ3 1Z95 2AM9 2AMA 2AMB 2AO6 2AX6 2AX7 2AX8 2AX9 2AXA
• Descriptor: ANDROGEN RECEPTOR, SULFATE ION, TESTOSTERONE, ... (5 entities in total)
• Functional Keywords: transcription, activation function 2 site (af2), small molecule inhibitor
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: P10275
• Total number of polymer chains: 1
• Total formula weight: 29708.87

Authors

AxerioCilies, P.,Lack, N.A.,ShashiNayana, M.R.,Chan, K.H.,Yeung, A.,LeBlanc, E.,Guns, E.,Rennie, P.,Cherkasov, A. (deposition date: 2011-04-28, release date: 2011-09-21, Last modification date: 2023-12-20)

Primary citation

Axerio-Cilies, P.,Lack, N.A.,Nayana, M.R.,Chan, K.H.,Yeung, A.,Leblanc, E.,Guns, E.S.,Rennie, P.S.,Cherkasov, A.
Inhibitors of Androgen Receptor Activation Function-2 (Af2) Site Identified Through Virtual Screening.
J.Med.Chem., 54:6197-, 2011

PubMed Abstract: The androgen receptor (AR) is one of the most studied drug targets for the treatment of prostate cancer. However, all current anti-androgens directly interact with the AR at the androgen binding site, which is prone to resistant mutations, calling for new strategies of the AR inhibition. The current study represents the first attempt to use virtual screening to identify inhibitors of activation function-2 (AF2) of the human AR. By combining large-scale docking with experimental approaches, we were able to identify several small molecules that interact with the AF2 and effectively prevent the transcriptional activation of the AR. The crystallographic structure of one of these inhibitors in complex with the AR provides critical insight into the corresponding protein-ligand interactions and suitable for future hit optimization. Taken together, our results provide a promising ground for development of novel anti-androgens that can help to address the problem of drug resistance in prostate cancer.

PubMed: 21846139
DOI: 10.1021/JM200532B

Experimental method

X-RAY DIFFRACTION (2.2 Å)