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.

Combined Pharmacophore and Grid-Independent Molecular Descriptors (GRIND) Analysis to Probe 3D Features of Inositol 1,4,5-Trisphosphate Receptor (IP3R) Inhibitors in Cancer

“…In site-directed mutagenic studies, the arginine and lysine residues were found to be important in the binding of ligands within the IP 3 R domain [ 72 , 73 ], wherein the residues including Arg-266, Lys-507, Arg-510, and Lys-569 were reported to be crucial. The docking poses of the selected hits were further strengthened by previous study where IP 3 R antagonists interacted with Arg-503 (π–π interactions and hydrogen bond), Ser-278 (hydrogen-bond acceptor interactions), and Lys-507 (surface contacts and hydrogen-bond acceptor interactions) [ 74 ].…”

“…Similarly, the Arg-266, Ser-278, Arg-510, and Tyr-567 residues present in the binding core of IP 3 R were found to be involved in the hydrophobic interactions ( Figure 9 ). Previously, Arg-266 was determined as an important facilitator of hydrophobic interactions [ 74 ].…”

“…Here, the molecular boundaries of the hydrophobic groups were suggested with the combination of a steric hotspot. Considering the important role of Arg-266 and Arg-510 in the binding core of IP 3 R [ 74 ], the presence of a steric hotspot along with a hydrophobic region represented the hydrophobic interactive nature of the receptor-binding site. The shape complementarity of the Tip contour defined by GRIND may be supported by the presence of Arg-266 in the β-trefoil (226–435) region and Tyr-567 in the α-helix (436–604) region of the IP 3 R-binding core ( Figure 9 ) [ 30 , 31 ].…”

“…Recently, hydrophobic and surface contacts of antagonists were found with the Arg-266, Thr-268, Ser-278, Lys-507, and Tyr-569 backbone and side-chain amino acid residues. However, Arg-266, Arg-510, and Ser-278 residues were found to be involved in π–π interactions specifically [ 74 ].…”

“…Arginine residues (Arg-510, Arg-266, and Arg-270) were predominantly present and broadly distributed throughout the IP 3 R-binding core ( Figure S12 ), providing α-amino nitrogen on their side chains and allowing the ligand to interact via hydrogen-bond donor and acceptor interactions. This was further strengthened by the binding pattern of IP 3 where residues in β domain-mediated hydrogen-bond interactions by anchoring the phosphate group at position R 4 within the binding core of IP 3 R [ 74 , 90 , 96 ]. In previous studies, an extensive hydrogen-bond network was observed between the phosphate group at position R 5 and Arg-266, Thr-267, Gly-268, Arg-269, Arg-504, Lys-508, and Tyr-569 [ 74 , 96 , 97 ].…”