A Molecular Modeling Study of the Hydroxyflutamide Resistance Mechanism Induced by Androgen Receptor Mutations
| Autor: | Hongli Liu, Hai-Yang Zhong, Tian-Qing Song, Jiazhong Li |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Agonist medicine.medical_specialty hydroxyflutamide medicine.drug_class Mutant Molecular mechanics Article Catalysis Flutamide lcsh:Chemistry Inorganic Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine drug resistance androgen receptor molecular dynamics simulation MM-GBSA Internal medicine Coactivator medicine Humans Physical and Theoretical Chemistry Binding site lcsh:QH301-705.5 Molecular Biology Spectroscopy Binding Sites Chemistry Organic Chemistry Androgen Antagonists General Medicine Computer Science Applications Cell biology Molecular Docking Simulation Androgen receptor 030104 developmental biology Endocrinology lcsh:Biology (General) lcsh:QD1-999 Receptors Androgen 030220 oncology & carcinogenesis Mutation Hydroxyflutamide Protein Binding |
| Zdroj: | International Journal of Molecular Sciences, Vol 18, Iss 9, p 1823 (2017) International Journal of Molecular Sciences International Journal of Molecular Sciences; Volume 18; Issue 9; Pages: 1823 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms18091823 |
| Popis: | Hydroxyflutamide (HF), an active metabolite of the first generation antiandrogen flutamide, was used in clinic to treat prostate cancer targeting androgen receptor (AR). However, a drug resistance problem appears after about one year’s treatment. AR T877A is the first mutation that was found to cause a resistance problem. Then W741C_T877A and F876L_T877A mutations were also reported to cause resistance to HF, while W741C and F876L single mutations cannot. In this study, molecular dynamics (MD) simulations combined with the molecular mechanics generalized Born surface area (MM-GBSA) method have been carried out to analyze the interaction mechanism between HF and wild-type (WT)/mutant ARs. The obtained results indicate that AR helix 12 (H12) plays a pivotal role in the resistance of HF. It can affect the coactivator binding site at the activation function 2 domain (AF2, surrounded by H3, H4, and H12). When H12 closes to the AR ligand-binding domain (LBD) like a lid, the coactivator binding site can be formed to promote transcription. However, once H12 is opened to expose LBD, the coactivator binding site will be distorted, leading to invalid transcription. Moreover, per-residue free energy decomposition analyses indicate that N705, T877, and M895 are vital residues in the agonist/antagonist mechanism of HF. |
| Databáze: | OpenAIRE |
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