Pharmacoinformatic Approaches to Design Potential Inhibitors of Inositol 1, 4, 5- Trisphosphate Receptor (IP3R) in Cancer

Abstract

Calcium ion (Ca+2) transport within cell plays a critical role in different physiological processes including metabolism and bioenergetics, cell division, cell autophagy and apoptosis thereby determines the cell fate. Inositol 1, 4, 5- trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Inositol 1, 4, 5-trisphosphate receptor (IP3R) residing on endoplasmic reticulum membrane is mainly responsible for constitute Ca+2 ion shuffling between major calcium store organelle the endoplasmic reticulum (ER) and the mitochondria. In mitochondria calcium has crucial role in ATP production therefore, maintaining an adequate calcium level in endoplasmic reticulum (ER) store and mitochondrial matrix through IP3R flux is essential in cell‟s bioenergetics process. Remodeling Ca2+ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Cancer cells have craving for high calcium flux via IP3R for restricted apoptosis and enhanced cell proliferation. Therefore inhibition of calcium flux from endoplasmic reticulum to mitochondria by small drug like molecules is promising concept in chemotherapeutic treatment in cancer. To understand underlying molecular mechanism of IP3R channel inhibition upon drug like molecules binding that induce conformational changes it is necessary to shed light on 3D structural features of IP3R. In present study, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models to elucidate the 3D structural features of IP3R modulators. 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.

Abstract

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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. Our pharmacophore model illuminates the existence of two hydrogen-bond acceptors (2.62 Å and 4.79 Å) and two hydrogen-bond donors (5.56 Å and 7.68 Å), respectively, from a hydrophobic group within the chemical scaffold, which may enhance the liability (IC50) of a compound for IP3R inhibition. Moreover, our GRIND model (PLS: Q2 = 0.70

and R2 = 0.72) further strengthens the identified Pharmacophore features of IP3R modulators by probing the presence of complementary hydrogen-bond donor and hydrogen-bond acceptor hotspots at a distance of 7.6–8.0 Å and 6.8–7.2 Å, respectively, from a hydrophobic hotspot at the virtual receptor site (VRS). The identified 3D structural features of IP3R modulators were used to screen (virtual screening) the ChemBridge database, the National Cancer Institute (NCI) database, and natural compounds from the ZINC database. Finally selected potential hits (antagonists) against IP3R include, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer. Early detection of cancer and excision is eminent requirement of pharmaceutical industry therefore; this research will increase our understanding of the role of calcium signals in underlying molecular mechanism of cancer that could pave the way towards systematic control of cancer cell proliferation. Computational studies will aid in the structural insight of channel activity and inhibition not known previously by optimizing small molecule bindings in already available crystal structures to design more potent drugs.