Jia-Zhong Li and Gary A. Piazza Received: 17 September 2021 Accepted: 24 November 2021 Published
Jia-Zhong Li and Gary A. Piazza Received: 17 September 2021 Accepted: 24 November 2021 Published: 30 NovemberAbstract: Inositol 1, four, 5-trisphosphate receptor (IP3 R)-mediated Ca2+ signaling plays a pivotal function in different cellular processes, such as cell proliferation and cell death. Remodeling Ca2+ signals by targeting the downstream effectors is regarded an important hallmark in cancer progression. Regardless of recent structural analyses, no binding hypothesis for antagonists inside the IP3 -binding core (IBC) has been proposed but. As a result, to elucidate the 3D structural options of IP3 R modulators, we used combined pharmacoinformatic approaches, including ligand-based pharmacophore models and grid-independent molecular descriptor (GRIND)-based models. Our pharmacophore model illuminates the existence of two PIM1 Inhibitor supplier hydrogen-bond acceptors (2.62 and 4.79 and two hydrogen-bond donors (5.56 and 7.68 , respectively, from a hydrophobic group within the chemical scaffold, which could improve the liability (IC50 ) of a compound for IP3 R inhibition. Furthermore, our GRIND model (PLS: Q2 = 0.70 and R2 = 0.72) additional strengthens the identified pharmacophore options of IP3 R modulators by probing the presence of complementary hydrogen-bond donor and hydrogenbond acceptor hotspots at a distance of 7.6.0 and 6.8.two respectively, from a hydrophobic hotspot at the virtual receptor web page (VRS). The identified 3D structural characteristics of IP3 R modulators had been utilized to screen (virtual screening) 735,735 compounds from the ChemBridge database, 265,242 compounds in the National Cancer Institute (NCI) database, and 885 organic compounds in the ZINC database. Following the application of Nav1.4 Inhibitor Gene ID filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as prospective hits (antagonists) against IP3 R. The identified hits could further assist within the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer. Keywords: IP3 R-mediated Ca2+ signaling; IP3 R modulators; pharmacophore modeling; virtual screening; hits; GRIND model; PLS co-efficient correlogramPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.1. Introduction Inositol 1, 4, 5-trisphosphate receptor (IP3 R)-mediated Ca2+ signaling is an essential regulatory factor in cancer progression, such as invasiveness and cell proliferation [1]. In carcinogenesis, the Ca2+ signals are remodeled to regulate the cell cycle by inducing the early response genes (JUN and FOS) in the G1 phase and possess a direct influence on cell death [2]. Hence, the response of malignant cell is overwhelmed by Ca2+ signaling by supplying them an unconditional advantage of unrestricted cell multiplication and proliferation [5,6], avoiding programmed cell death [7,8], and offering particular adaptations to limited cellular circumstances. For that reason, Ca2+ signals are known to facilitate metastasis from the key point of initiation [9,10]. Nonetheless, remodeling of Ca2+ signaling by downstream Ca2+ -dependent effectors is deemed a prime cause for sustaining the cancer hallmark [11,12]. Cancer cells depend on the constitutive Ca2+ transfer from the endoplasmic reticulum (ER) to mitochondria to sustain their higher stipulation of developing blocks for ATP productionCopyright: 2021 by the authors. Licensee MDPI, Basel, Switzerland. This short article is an open access write-up distributed under.