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
. 2024 Oct 19;25(20):11250.
doi: 10.3390/ijms252011250.

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

Wenqing Jia  1   2 , Jingdian Liu  1 , Xianchao Cheng  2 , Xingguo Li  3 , Yukui Ma  1   4
Affiliations

In Silico Discovery of a Novel PI3Kδ Inhibitor Incorporating 3,5,7-Trihydroxychroman-4-one Targeting Diffuse Large B-Cell Lymphoma

Wenqing Jia et al. Int J Mol Sci. .

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and it is highly aggressive and heterogeneous. Targeted therapy is still the main treatment method used in clinic due to its lower risk of side effects and personalized medication. Excessive activation of PI3Kδ in DLBCL leads to abnormal activation of the PI3K/Akt pathway, promoting the occurrence and development of DLBCL. The side effects of existing PI3Kδ inhibitors limit their clinical application. The discovery of PI3Kδ inhibitors with novel structures and minimal side effects is urgently needed. This study constructed a PI3Kδ inhibitor screening model to screen natural product libraries. Revealing the mechanism of natural product therapy for DLBCL through network pharmacology, kinase assays, and molecular dynamics. The results of molecular docking indicated that Silibinin had a high docking score and a good binding mode with PI3Kδ. The results of network pharmacology indicated that Silibinin could exert therapeutic effects on DLBCL by inhibiting PI3Kδ activity and affecting the PI3K/Akt pathway. The kinase assays indicated that Silibinin concentration dependently inhibited the activity of PI3Kδ. The results of molecular dynamics indicated that Silibinin could stably bind to PI3Kδ. Silibinin was a structurally novel 3,5,7-trihydroxychroman-4-one PI3Kδ inhibitor, providing valuable information for the subsequent discovery of PI3Kδ inhibitors.

Keywords: DLBCL; PI3Kδ; molecular dynamics; network pharmacology; virtual screening.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflicts of interest in this article.

Figures

Figure 1
Figure 1
Schematic diagram of the PI3K/Akt/mTOR signaling pathway (By Figdraw).
Figure 2
Figure 2
Chemical structures of some reported PI3Kδ inhibitors.
Figure 3
Figure 3
The flow chart of the discovery of PI3Kδ inhibitors (By Figdraw).
Figure 4
Figure 4
(A) 2D diagram of the interaction between Silibinin and PI3Kδ. (B) 2D diagram of the interaction between Epigallocatechin gallate-PI3Kδ. (C) 2D diagram of the interaction between Chicolic acid-PI3Kδ. (D) 2D diagram of Vitexin-PI3Kδ interaction. (E) 2D diagram of the Cynaroside-PI3Kδ interaction. (F) 2D diagram of Idelalisib-PI3Kδ interaction.
Figure 5
Figure 5
Binding patterns of Silibinin–PI3Kδ and Idelalisib-PI3Kδ, Silibinin (blue) and Idelalisib (red). (A) The active pocket site map of PI3Kδ. (B) 3D image of Silibinin binding to PI3Kδ active pocket. (C) 3D image of Silibinin–PI3Kδ interaction. (D) 3D image of Idelalisib binding to PI3Kδ active pocket. (E) 3D image of Idelalisib-PI3Kδ interaction.
Figure 6
Figure 6
Network pharmacology analysis of Silibinin and DLBCL. (A) Venn diagram showing the intersecting genes between Silibinin and DLBCL. (B) The PPI network by STRING. (C) The nine core targets obtained by Crntiscape2.2. (D) Gene ontology functional enrichment analysis. BP: Biological process; CC: Cell component; MF: Molecular function. (E) KEGG pathway analysis of the intersecting genes. The red box represented the key pathway of Silibinin in the treatment of DLBCL.
Figure 7
Figure 7
The docking hotmap of Silibinin with core targets.
Figure 8
Figure 8
Inhibition of PI3Kδ by Silibinin. Data are presented as the mean ± SD (n = 3).
Figure 9
Figure 9
(A) The RMSD trajectories of the PI3Kδ/PI3Kδ−Silibinin systems during 100 ns simulations. (B) The RMSF maps of PI3Kδ/PI3Kδ–Silibinin systems during simulations. The red box represented key amino acid residues. (C) The variation curve of SASA during 100 ns simulations. (D) The variation curve of Rg during 100 ns simulations.
Figure 10
Figure 10
(A) The curve of the number of H-bonds during 100 ns simulations. (B) Residual contribution energy of the interaction between PI3Kδ and Silibinin.
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Bian W., Li H., Chen Y., Yu Y., Lei G., Yang X., Li S., Chen X., Li H., Yang J., et al. Ferroptosis mechanisms and its novel potential therapeutic targets for DLBCL. Biomed Pharmacother. 2024;173:116386. doi: 10.1016/j.biopha.2024.116386. - DOI - PubMed
    1. Scarfì F., Magnaterra E., Santini S., Taviti F. Klinefelter syndrome and cutaneous localization of diffuse large B cell lymphoma: A real connection or a casual association? Dermatol. Rep. 2023;16:9812. doi: 10.4081/dr.2023.9812. - DOI - PMC - PubMed
    1. Uddin S., Hussain A.R., Siraj A.K., Manogaran P.S., Al-Jomah N.A., Moorji A., Atizado V., Al-Dayel F., Belgaumi A., El-Solh H., et al. Role of phosphatidylinositol 3’-kinase/AKT pathway in diffuse large B-cell lymphoma survival. Blood. 2006;108:4178–4186. doi: 10.1182/blood-2006-04-016907. - DOI - PubMed
    1. Liu J., Chang Y.T., Kou Y.Y., Zhang P.P., Dong Q.L., Guo R.Y., Liu L.Y., Lin H.W., Yang F. Marine sponge-derived alkaloid inhibits the PI3K/AKT/mTOR signaling pathway against diffuse large B-cell lymphoma. Med. Oncol. 2024;41:212. doi: 10.1007/s12032-024-02448-9. - DOI - PubMed
    1. Wu W., Xia X., Tang L., Luo J., Xiong S., Ma G., Lei H. Phosphoinositide 3-kinase as a therapeutic target in angiogenic disease. Exp. Eye Res. 2023;236:109646. doi: 10.1016/j.exer.2023.109646. - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources