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Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening

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Abstract

Anterior Gradient 2 (AGR2) has recently been reported as a tumor biomarker in various cancers, i.e., breast, prostate and lung cancer. Predominantly, AGR2 exists as a homodimer via a dimerization domain (E60-K64); after it is self-dimerized, it helps FGF2 and VEGF to homo-dimerize and promotes the angiogenesis and the invasion of vascular endothelial cells and fibroblasts. Up till now, no small molecule has been discovered to inhibit the AGR2–AGR2 homodimer. Therefore, the present study was performed to prepare a validated 3D structure of AGR2 by homology modeling and discover a small molecule by screening the FDA-approved drugs library on AGR2 homodimer as a target protein. Thirteen different homology models of AGR2 were generated based on different templates which were narrowed down to 5 quality models sorted by their overall Z-scores. The top homology model based on PDB ID = 3PH9 was selected having the best Z-score and was further assessed by Verify-3D, ERRAT and RAMPAGE analysis. Structure-based virtual screening narrowed down the large library of FDA-approved drugs to ten potential AGR2–AGR2 homodimer inhibitors having FRED score lower than − 7.8 kcal/mol in which the top 5 drugs’ binding stability was counter-validated by molecular dynamic simulation. To sum up, the present study prepared a validated 3D structure of AGR2 and, for the first time reported the discovery of 5 FDA-approved drugs to inhibit AGR2–AGR2 homodimer by using structure-based virtual screening. Moreover, the binding of the top 5 hits with AGR2 was also validated by molecular dynamic simulation.

Graphic abstract

A validated 3D structure of Anterior Gradient 2 (AGR2) was prepared by homology modeling, which was used in virtual screening of FDA-approved drugs library for the discovery of prospective inhibitors of AGR2–AGR2 homodimer.

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Acknowledgements

All the authors acknowledge the "OpenEye Scientific Software" for providing a free academic license to perform in silico studies. The principal author is grateful to Professor Huchen Zhou and Professor Dawei Li for deep insights into the project.

Funding

The lead author Shafi Ullah acknowledges China Scholarship Council (CSC) for funding this project.

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Author notes

  1. Shafi Ullah and Shafi Ullah Khan have contributed equally to this work

Authors and Affiliations

  1. Department of Medicinal Chemistry, School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Shafi Ullah & Yaxue Zhao

  2. School of Pharmacy - Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, 47500, Subang Jaya, Selangor, Malaysia

    Shafi Ullah Khan & Thet Thet Htar

  3. Department of Bioinformatics and Biological Statistics, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Abbas Khan

  4. Department of Biochemistry, Abdul Wali Khan University, Mardan, 23200, Pakistan

    Muhammad Junaid, Humaira Rafiq & Abdul Wadood

  5. Department of Pharmacy, Abasyn University, Ring Road, Peshawar, 25120, Pakistan

    Shafi Ullah Khan

  6. Faculty of Pharmacy, Atta-Ur-Rahman Institute for Natural Products Discovery (AuRIns), Universiti Teknologi MARA, Bandar Puncak Alam, Selangor Darul Ehsan, Malaysia

    Syed Adnan Ali Shah

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  1. Shafi Ullah
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Ullah, S., Khan, S.U., Khan, A. et al. Prospect of Anterior Gradient 2 homodimer inhibition via repurposing FDA-approved drugs using structure-based virtual screening. Mol Divers 26, 1399–1409 (2022). https://doi.org/10.1007/s11030-021-10263-x

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