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
. 2016 Sep 21;21(9):1259.
doi: 10.3390/molecules21091259.

Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

Fang Lu  1 , Ganggang Luo  2 , Liansheng Qiao  3 , Ludi Jiang  4 , Gongyu Li  5 , Yanling Zhang  6
Affiliations

Virtual Screening for Potential Allosteric Inhibitors of Cyclin-Dependent Kinase 2 from Traditional Chinese Medicine

Fang Lu et al. Molecules. .

Abstract

Cyclin-dependent kinase 2 (CDK2), a member of Cyclin-dependent kinases (CDKs), plays an important role in cell division and DNA replication. It is regarded as a desired target to treat cancer and tumor by interrupting aberrant cell proliferation. Compared to lower subtype selectivity of CDK2 ATP-competitive inhibitors, CDK2 allosteric inhibitor with higher subtype selectivity has been used to treat CDK2-related diseases. Recently, the first crystal structure of CDK2 with allosteric inhibitor has been reported, which provides new opportunities to design pure allosteric inhibitors of CDK2. The binding site of the ATP-competition inhibitors and the allosteric inhibitors are partially overlapped in space position, so the same compound might interact with the two binding sites. Thus a novel screening strategy was essential for the discovery of pure CDK2 allosteric inhibitors. In this study, pharmacophore and molecular docking were used to screen potential CDK2 allosteric inhibitors and ATP-competition inhibitors from Traditional Chinese Medicine (TCM). In the docking result of the allosteric site, the compounds which can act with the CDK2 ATP site were discarded, and the remaining compounds were regarded as the potential pure allosteric inhibitors. Among the results, prostaglandin E1 and nordihydroguaiaretic acid (NDGA) were available and their growth inhibitory effect on human HepG2 cell lines was determined by MTT assay. The two compounds could substantially inhibit the growth of HepG2 cell lines with an estimated IC50 of 41.223 μmol/L and 45.646 μmol/L. This study provides virtual screening strategy of allosteric compounds and a reliable method to discover potential pure CDK2 allosteric inhibitors from TCM. Prostaglandin E1 and NDGA could be regarded as promising candidates for CDK2 allosteric inhibitors.

Keywords: CDK2; TCM; allosteric inhibitors; molecular docking; pharmacophore.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Virtual screening strategy of this study.
Figure 2
Figure 2
The optimal GALAHAD pharmacophore model of CDK2 allosteric inhibitors (A) and the allosteric compound BAS00380830 mapped with the optimal GALAHAD pharmacophore model (B). AA means hydrogen bond acceptors; HY means hydrophobic features; NP means positive nitrogen.
Figure 3
Figure 3
The best HipHop pharmacophore model of CDK2 ATP-competitive inhibitors (A) and the compound BDBM50394183 mapped with model Hypo1-1 (B).
Figure 4
Figure 4
Docking results between Staurosporine (A); Dinaciclib (B); and Roscovitine (C) and CDK2 ATP binding site.
Figure 5
Figure 5
Pharmacophore mapping results and molecular docking results of prostaglandin E1 and nordihydroguaiaretic acid.
Figure 6
Figure 6
Effect of prostaglandin E1 and NDGA on cell proliferation in cultured HepG2 cells.
Figure 7
Figure 7
Chemical structures and IC50 of the compounds in the training set for the construction of GALAHAD pharmacophore model.
Figure 8
Figure 8
Chemical information of the training set for the HipHop pharmacophore model generation.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Asghar U., Witkiewicz A.K., Turner N.C., Knudsen E.S. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat. Rev. Drug Discov. 2015;14:130–146. doi: 10.1038/nrd4504. - DOI - PMC - PubMed
    1. Zhang J., Yang P.L., Gray N.S. Targeting cancer with small molecule kinase inhibitors. Nat. Rev. Cancer. 2009;9:28–39. doi: 10.1038/nrc2559. - DOI - PubMed
    1. Ortega S., Malumbres M., Barbacid M. Cyclin d-dependent kinases, INK4 inhibitors and cancer. Biochim. Biophys. Acta. 2002;1602:73–87. doi: 10.1016/S0304-419X(02)00037-9. - DOI - PubMed
    1. Lapenna S., Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat. Rev. Drug Discov. 2009;8:547–566. doi: 10.1038/nrd2907. - DOI - PubMed
    1. Echalier A., Endicott J.A., Noble M.E.M. Recent developments in cyclin-dependent kinase biochemical and structural studies. Biochim. Biophys. Acta. 2010;1804:511–519. doi: 10.1016/j.bbapap.2009.10.002. - DOI - PubMed