In silico study of androgen receptor N-terminal domain and exploration of its modulators

Abstract

The androgen receptor (AR, Uniprot: P10275) signaling plays a key role in the progression of prostate cancer, various AR-related ligands have been reported to treat prostate cancer. However, some resistance mechanisms limited the treating effect of these ligands. Since DBD binding or the allosteric binding sites in LBD of AR may allow the circumvention of some drug resistance mechanisms, anti-resistance is expected especially through the NTD (N-terminal domain) targeting. What’s more, studies have shown that compounds including EPI-001 and its derivatives which bind to the Tau-5 region on NTD could be promising molecules for AR-based therapeutics. Herein, we employed aMD (accelerated molecular dynamics) simulation to fold Tau-5 unit proteins into native structure correctly. Subsequently, based on the predicted structural features of Tau-5, the virtual screening was conducted to discover new compounds targeting AR-NTD. We picked up 8 compounds (according to their docking scores and partly similar structural consists as known AR ligands) and analyzed their interaction with Tau-5, compared with the positive control EPI-001, four of the pick-up compounds showed better glide scores. Interestingly, although compound 8 had a lower docking score, it consisted of a similar component as the ligand EIQPN and the amide derivatives, this predicts that compound 8 has also the potential to be modified into an excellent AR-NTD binding molecule. These 8 compounds were all commercially available and could be tested to check whether there was a hit compound to bind the AR-NTD and to regulate its bio-activities. Together, this study described an in silico VLS approach to discover AR-NTD ligands and provided more choices for developing AR-targeted therapies.

Communicated by Ramaswamy H. Sarma

Keywords:

• Androgen receptor
• accelerated molecular dynamics
• virtual screening

Authors’ contributions

Conceptualization, Weidong Zhang, Jiangang Huang and Wenjun Du; Formal analysis, Weidong Zhang, Yalan Zhu and Wenjun Du; Funding acquisition, Weidong Zhang and Hongyu Hu; Investigation, Jiangang Huang and Hongyu Hu; Methodology, Weidong Zhang, Yalan Zhu, Wenjun Du and Hongyu Hu; Project administration, Weidong Zhang, Yiling He and Hongyu Hu; Validation, Weidong Zhang, Jiangang Huang, Yalan Zhu and Yiling He; Writing—original draft, Jiangang Huang, Wenjun Du and Hongyu Hu; Writing—review & editing, Weidong Zhang, Jiangang Huang and Yiling He.

Data availability statement

The data were available on request from the corresponding authors.

Disclosure statement

The authors declare no conflicts of interest.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was funded by the special scientific research fund project for basic research of Jinhua Municipal Central Hospital (JY2020-6-07) (JY2020-6-09), and the Science and Technology Project of Jinhua (2021-3-108).