Sharma Satvika, Saini Sandeep, Chadha Vijayta Dani, Saini Avneet, Dhawan Devinder Kumar
Department of Biophysics, Panjab University, Chandigarh, India.
Department of Bioinformatics, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh, India.
Cell Biochem Biophys. 2025 Jun 13. doi: 10.1007/s12013-025-01797-0.
Gliomas, the primary brain tumors, are derived from glial cells and encompass the majority of malignancies of the central nervous system (CNS). CNS is an important target for androgens, which act through the intercession of androgen receptor (AR). AR signaling following activation of AR plays an important role in the growth of tumors and AR expression is altered in many cancers including glioma. The strategy of targeting AR for the treatment of glioma has gained interest. However, AR antagonists are not suitable for aggressive glioma due to its heterogeneous nature. Selective androgen receptor modulators (SARMs) display several advantages over traditional antagonists by offering varying degrees of agonist and antagonist effects. In the present study, blind docking and binding affinity analysis of 20 SARMs was performed using AutoDock vina. Out of all the molecules, MK-2866 (Ostarine) was perceived to bind to AF-1 region in the N-terminal domain (NTD) of AR protein with binding affinity of-9.4 Kcal/mol, thereby making it a prime candidate for further study. The Molecular dynamics (MD) simulations and MM-PBSA analysis revealed that Ostarine exhibits strong and stable binding affinity towards AR. The IC50 value of Ostarine demonstrated a twofold-increase in the inhibition of C6 cells as compared to Bicalutamide. Further, cell viability, cell migration and cell invasion assays indicated the potential of Ostarine as an AR antagonist that holds chemotherapeutic promise in containing the propagation of gliomas C6 cells.
胶质瘤是原发性脑肿瘤，起源于神经胶质细胞，是中枢神经系统（CNS）中最常见的恶性肿瘤。中枢神经系统是雄激素的重要作用靶点，雄激素通过雄激素受体（AR）发挥作用。AR激活后的信号传导在肿瘤生长中起重要作用，并且在包括胶质瘤在内的许多癌症中AR表达都会发生改变。针对AR治疗胶质瘤的策略已引起关注。然而，由于其异质性，AR拮抗剂不适用于侵袭性胶质瘤。选择性雄激素受体调节剂（SARM）通过提供不同程度的激动剂和拮抗剂作用，显示出优于传统拮抗剂的几个优点。在本研究中，使用AutoDock vina对20种SARM进行了盲对接和结合亲和力分析。在所有分子中，MK-2866（奥司他丁）被认为与AR蛋白N端结构域（NTD）中的AF-1区域结合，结合亲和力为-9.4千卡/摩尔，因此使其成为进一步研究的主要候选物。分子动力学（MD）模拟和MM-PBSA分析表明，奥司他丁对AR表现出强烈且稳定的结合亲和力。与比卡鲁胺相比，奥司他丁的IC50值在抑制C6细胞方面提高了两倍。此外，细胞活力、细胞迁移和细胞侵袭试验表明，奥司他丁作为AR拮抗剂具有潜力，有望在抑制胶质瘤C6细胞增殖方面发挥化疗作用。
