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Scaffold Hopping and Screening for Potent Small Molecule Agonists for GRP94: Implications to Alleviate ER Stress-Associated Pathogenesis

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Abstract

Disparity in the activity of Endoplasmic reticulum (ER) leads to degenerative diseases, mainly associated with protein misfolding and aggregation leading to cellular dysfunction and damage, ultimately contributing to ER stress. ER stress activates the complex network of Unfolded Protein Response (UPR) signaling pathways mediated by transmembrane proteins IRE1, ATF6, and PERK. In addition to UPR, many ER chaperones have evolved to optimize the output of properly folded secretory and membrane proteins. Glucose-regulated protein 94 (GRP94), an ER chaperone of heat shock protein HSP90 family, directs protein folding through interaction with other components of the ER protein folding machinery and assists in ER-associated degradation (ERAD). Activation of GRP94 would increase the efficacy of protein folding machinery and regulate the UPR pathway toward homeostasis. The present study aims to screen for novel agonists for GRP94 based on Core hopping, pharmacophore hypothesis, 3D-QSAR, and virtual screening with small-molecule compound libraries in order to improve the efficiency of native protein folding by enhancing GRP94 chaperone activity, therefore to reduce protein misfolding and aggregation. In this study, we have employed the strategy of small molecule-dependent ER programming to enhance the chaperone activity of GRP94 through scaffold hopping-based screening approach to identify specific GRP94 agonists. New scaffolds generated by altering the cores of NECA, the known GRP94 agonist, were validated by employing pharmacophore hypothesis testing, 3D-QSAR modeling, and molecular dynamics simulations. This facilitated the identification of small molecules to improve the efficiency of native protein folding by enhancing GRP94 activity. High-throughput virtual screening of the selected pharmacophore hypothesis against Selleckchem and ZINC databases retrieved a total of 2,27,081 compounds. Further analysis on docking and ADMET properties revealed Epimedin A, Narcissoside, Eriocitrin 1,2,3,4,6-O-Pentagalloylglucose, Secoisolariciresinol diglucoside, ZINC92952357, ZINC67650204, and ZINC72457930 as potential lead molecules. The stability and interaction of these small molecules were far better than the known agonist, NECA indicating their efficacy in selectively alleviating ER stress-associated pathogenesis. These results substantiate the fact that small molecule-dependent ER reprogramming would activate the ER chaperones and therefore reduce the protein misfolding as well as aggregation associated with ER stress in order to restore cellular homeostasis.

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Abbreviations

ER:

Endoplasmic reticulum

UPR:

Unfolded protein response

IRE1:

Inositol-requiring ER-to-nucleus signal kinase 1

PERK:

Protein kinase-like ER kinase

GRP94:

Glucose-regulated protein 94

QSAR:

Quantitative structure–activity relationship

MD:

Molecular dynamics

RMSD:

Root mean square deviation

RMSF:

Root mean square fluctuation

ROS:

Reactive oxygen species

ADMET:

Absorption, distribution, metabolism, excretion, and toxicity

MDCK:

Madin–Darby canine kidney cells

fs:

Femtosecond

ns:

Nanosecond

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Funding

The authors are grateful to Department of Biotechnology (DBT), Ministry of Science and Technology, New Delhi, India for providing the necessary research support to carry out this study (Ref: BT/PR30828/MED/97/434/2018 dated 26.09.2019).

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Authors and Affiliations

  1. Department of Bioinformatics, Bharathiar University, Coimbatore, Tamil Nadu, India

    Shoufia Jabeen Mubarak & Hemamalini Vedagiri

  2. Department of Reproductive Biology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110029, India

    Surabhi Gupta

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Mubarak, S.J., Gupta, S. & Vedagiri, H. Scaffold Hopping and Screening for Potent Small Molecule Agonists for GRP94: Implications to Alleviate ER Stress-Associated Pathogenesis. Mol Biotechnol 66, 737–755 (2024). https://doi.org/10.1007/s12033-023-00685-3

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