Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun;26(3):1399-1409.
doi: 10.1007/s11030-021-10263-x. Epub 2021 Jun 28.

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

Shafi Ullah #  1 , Shafi Ullah Khan #  2   3 , Abbas Khan  4 , Muhammad Junaid  5 , Humaira Rafiq  5 , Thet Thet Htar  2 , Yaxue Zhao  6 , Syed Adnan Ali Shah  7 , Abdul Wadood  8
Affiliations

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

Shafi Ullah et al. Mol Divers. 2022 Jun.

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. 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.

Keywords: AGR2 homodimer; Cancer; Dimer inhibitor; Drug repositioning; Virtual screening.

PubMed Disclaimer

References

    1. Park SW, Zhen G, Verhaeghe C, Nakagami Y, Nguyenvu LT, Barczak AJ, Killeen N, Erle DJ (2009) The protein disulfide isomerase AGR2 is essential for production of intestinal mucus. Proc Natl Acad Sci 106:6950–6955. https://doi.org/10.1073/pnas.0808722106 - DOI - PubMed - PMC
    1. Tiemann K, Garri C, Lee SB, Malihi PD, Park M, Alvarez RM, Yap LP, Mallick P, Katz JE, Gross ME (2019) Loss of ER retention motif of AGR2 can impact mTORC signaling and promote cancer metastasis. Oncogene 38:3003–3018. https://doi.org/10.1038/s41388-018-0638-9 - DOI - PubMed
    1. Jia M, Guo Y, Zhu D, Zhang N, Li L, Jiang J, Dong Y, Xu Q, Zhang X, Wang M (2018) Pro-metastatic activity of AGR2 interrupts angiogenesis target bevacizumab efficiency via direct interaction with VEGFA and activation of NF-κB pathway. Biochim. Biophys. Acta. Mol Basis Dis 1864:1622–1633. https://doi.org/10.1016/j.bbadis.2018.01.021 - DOI
    1. Chevet E, Fessart D, Delom F, Mulot A, Vojtesek B, Hrstka R, Murray E, Gray T, Hupp T (2013) Emerging roles for the pro-oncogenic anterior gradient-2 in cancer development. Oncogene 32:2499–2509. https://doi.org/10.1038/onc.2012.346 - DOI - PubMed
    1. Brychtova V, Vojtesek B, Hrstka R (2011) Anterior gradient 2: a novel player in tumor cell biology. Cancer lett 304:1–7. https://doi.org/10.1016/j.canlet.2010.12.023 - DOI - PubMed

LinkOut - more resources