Biological Regulatory Network (BRN) Analysis and Molecular Docking Simulations to Probe the Modulation of IP3R Mediated Ca2+ Signaling in Cancer

Abstract

Inositol trisphosphate receptor (IP₃R) mediated Ca⁺² signaling is essential in determining the cell fate by regulating numerous cellular processes, including cell division and cell death. Despite extensive studies about the characterization of IP₃R in cancer, the underlying molecular mechanism initiating the cell proliferation and apoptosis remained enigmatic. Moreover, in cancer, the modulation of IP₃R in downstream signaling pathways, which control oncogenesis and cancer progression, is not well characterized. Here, we constructed a biological regulatory network (BRN), and describe the remodeling of IP₃R mediated Ca²⁺ signaling as a central key that controls the cellular processes in cancer. Moreover, we summarize how the inhibition of IP₃R affects the deregulated cell proliferation and cell death in cancer cells and results in the initiation of pro-survival responses in resistance of cell death in normal cells. Further, we also investigated the role of stereo-specificity of IP₃ molecule and its analogs in binding with the IP₃ receptor. Molecular docking simulations showed that the hydroxyl group at R₆ position along with the phosphate group at R₅ position in ‘R’ conformation is more favorable for IP₃ interactions. Additionally, Arg-266 and Arg-510 showed π–π and hydrogen bond interactions and Ser-278 forms hydrogen bond interactions with the IP₃ binding site. Thus, they are identified as crucial for the binding of antagonists.