In silico and in vitro assessment of androgen receptor antagonists

Sercinoglu O., Bereketoglu C., Olsson P., Pradhan A.

COMPUTATIONAL BIOLOGY AND CHEMISTRY, cilt.92, 2021 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 92
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1016/j.compbiolchem.2021.107490
  • Dergi Adı: COMPUTATIONAL BIOLOGY AND CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Applied Science & Technology Source, BIOSIS, Biotechnology Research Abstracts, Chemical Abstracts Core, Chimica, Compendex, Computer & Applied Sciences, EMBASE, INSPEC, MEDLINE, zbMATH
  • Anahtar Kelimeler: Helix 12, Antiandrogen, Prostate, Endocrine disruption, Pollutants, ALTERS SEXUAL-DIFFERENTIATION, REPORTER GENE ASSAYS, MOLECULAR-DYNAMICS, MALE-RAT, RISK-ASSESSMENT, RAINBOW-TROUT, LINURON, PROCYMIDONE, ENDOCRINE, PESTICIDES
  • Marmara Üniversitesi Adresli: Hayır

Özet

There is a growing concern for male reproductive health as studies suggest that there is a sharp increase in prostate cancer and other fertility related problems. Apart from lifestyle, pollutants are also known to negatively affect the reproductive system. In addition to many other compounds that have been shown to alter androgen signaling, several environmental pollutants are known to disrupt androgen signaling via binding to androgen receptor (AR) or indirectly affecting the androgen synthesis. We analyzed here the molecular mechanism of the interaction between the human AR Ligand Binding Domain (hAR-LBD) and two environmental pollutants, linuron (a herbicide) and procymidone (a pesticide), and compared with the steroid agonist dihydrotestosterone (DHT) and well-known hAR antagonists bicalutamide and enzalutamide. Using molecular docking and dynamics simulations, we showed that the co-activator interaction site of the hAR-LBD is disrupted in different ways by different ligands. Binding free energies of the ligands were also ordered in increasing order as follows: linuron, procymidone, DHT, bicalutamide, and enzalutamide. These data were confirmed by in vitro assays. Reporter assay with MDA-kb2 cells showed that linuron, procymidone, bicalutamide and enzalutamide can inhibit androgen mediated activation of luciferase activity. Gene expression analysis further showed that these compounds can inhibit the expression of prostate specific antigen (PSA) and microseminoprotein beta (MSMB) in prostate cell line LNCaP. Comparative analysis showed that procymidone is more potent than linuron in inhibiting AR activity. Furthermore, procymidone at 10 mu M dose showed equivalent and higher activity to AR inhibitor enzalutamide and bicalutamide respectively.