Identification of natural products as novel PI3Kβ inhibitors through pharmacophore-based virtual screening

Xuemei Jin, Woosun Kwon, Tae Soo Kim, Jung Nyoung Heo, Hyuncheol Chung, Jiwon Choi, Kyoung Tai No

Research output: Contribution to journalArticle

Abstract

Phosphatidylinositol 3-kinase beta (PI3Kβ) is the dominant isoform of PI3K and has been implicated in thrombosis as well as phosphatase and tensin homologue-loss-induced tumorigenesis. PI3Kβ has been considered to be an attractive target for anticancer drug discovery, and several PI3Kβ inhibitors have progressed into clinical trials. Here, we disclose the discovery of two natural products (PBY-0002 and PBY0006) that have inhibitory effects on PI3Kβ. These two natural products were identified through pharmacophore-based virtual screening, molecular docking, and a molecular dynamics simulation. Furthermore, an in vitro assay against human gastric cancer cell lines revealed that these two compounds showed anticancer activity. To identify the binding modes of PBY-0002 and PBY-0006 further, we performed a systematical investigation with comparison to the binding mode of GSK2636711, which is a known PI3Kβ inhibitor. The results demonstrated that PBY-0002 and PBY-0006 were tightly embedded into the ATP-binding site via hydrogen bonds and π-cation interactions. These two natural products can provide a promising starting point for the rational design of potent analogs with inhibitory activity against PI3Kβ.

Original languageEnglish
Pages (from-to)294-299
Number of pages6
JournalBulletin of the Korean Chemical Society
Volume39
Issue number3
DOIs
Publication statusPublished - 2018 Mar 1

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Phosphatidylinositol 3-Kinase
Biological Products
Screening
Phosphoric Monoester Hydrolases
Molecular dynamics
Cations
Assays
Hydrogen bonds
Protein Isoforms
Adenosine Triphosphate
Binding Sites
Cells
Computer simulation

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Cite this

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title = "Identification of natural products as novel PI3Kβ inhibitors through pharmacophore-based virtual screening",
abstract = "Phosphatidylinositol 3-kinase beta (PI3Kβ) is the dominant isoform of PI3K and has been implicated in thrombosis as well as phosphatase and tensin homologue-loss-induced tumorigenesis. PI3Kβ has been considered to be an attractive target for anticancer drug discovery, and several PI3Kβ inhibitors have progressed into clinical trials. Here, we disclose the discovery of two natural products (PBY-0002 and PBY0006) that have inhibitory effects on PI3Kβ. These two natural products were identified through pharmacophore-based virtual screening, molecular docking, and a molecular dynamics simulation. Furthermore, an in vitro assay against human gastric cancer cell lines revealed that these two compounds showed anticancer activity. To identify the binding modes of PBY-0002 and PBY-0006 further, we performed a systematical investigation with comparison to the binding mode of GSK2636711, which is a known PI3Kβ inhibitor. The results demonstrated that PBY-0002 and PBY-0006 were tightly embedded into the ATP-binding site via hydrogen bonds and π-cation interactions. These two natural products can provide a promising starting point for the rational design of potent analogs with inhibitory activity against PI3Kβ.",
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Identification of natural products as novel PI3Kβ inhibitors through pharmacophore-based virtual screening. / Jin, Xuemei; Kwon, Woosun; Kim, Tae Soo; Heo, Jung Nyoung; Chung, Hyuncheol; Choi, Jiwon; No, Kyoung Tai.

In: Bulletin of the Korean Chemical Society, Vol. 39, No. 3, 01.03.2018, p. 294-299.

Research output: Contribution to journalArticle

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