A Computational and In Vitro Appraisal of Ostarine to Target Androgen Receptor in Glioma C6 Cells

Abstract

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.

Keywords: Androgen receptor; Glioma; Ostarine; SARM.