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

Humaira Ismatullah,Ishrat Jabeen

doi:10.3390/ijms222312993

Abstract

Inositol 1, 4, 5-trisphosphate receptor (IP3R)-mediated Ca2+ signaling plays a pivotal role in different cellular processes, including cell proliferation and cell death. Remodeling Ca2+ signals by targeting the downstream effectors is considered an important hallmark in cancer progression. Despite recent structural analyses, no binding hypothesis for antagonists within the IP3-binding core (IBC) has been proposed yet. Therefore, to elucidate the 3D structural features of IP3R 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 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) 735,735 compounds from the ChemBridge database, 265,242 compounds from the National Cancer Institute (NCI) database, and 885 natural compounds from the ZINC database. After the application of filters, four compounds from ChemBridge, one compound from ZINC, and three compounds from NCI were shortlisted as potential hits (antagonists) against IP3R. The identified hits could further assist in the design and optimization of lead structures for the targeting and remodeling of Ca2+ signals in cancer.

Highlights

IntroductionInositol 1, 4, 5-trisphosphate receptor (IP3 R)-mediated Ca2+ signaling is an important regulatory factor in cancer progression, including invasiveness and cell proliferation [1,2,3]
Inositol 1, 4, 5-trisphosphate receptor (IP3 R)-mediated Ca2+ signaling is an important regulatory factor in cancer progression, including invasiveness and cell proliferation [1,2,3].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 have a direct influence on cell death [2,3,4]
Class A consisted of inositol derivatives, where phosphate groups with different stereochemistry are attached at positions R1– R6

Summary

Introduction

Inositol 1, 4, 5-trisphosphate receptor (IP3 R)-mediated Ca2+ signaling is an important regulatory factor in cancer progression, including invasiveness and cell proliferation [1,2,3]. The Ca2+ signals are remodeled to regulate the cell cycle by inducing the early response genes (JUN and FOS) in the G1 phase and have a direct influence on cell death [2,3,4]. The response of malignant cell is overwhelmed by Ca2+ signaling by providing them an unconditional advantage of unrestricted cell multiplication and proliferation [5,6], avoiding programmed cell death [7,8], and providing specific adaptations to limited cellular conditions. Remodeling of Ca2+ signaling by downstream Ca2+ -dependent effectors is considered a prime reason for sustaining the cancer hallmark [11,12]. Among three isoforms of IP3 R (R1 , R2„ and R3 ), the subtype IP3 R3 is considered a leading participant in carcinogenesis, since its expression level is associated with the aggressive behavior of colorectal carcinoma cells [16]

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