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Identification of Natural Products as Novel PI3KβInhibitors ThroughPharmacophore-based Virtual Screening

Authors
 Xuemei Jin  ;  Woosun Kwon  ;  Tae Soo Kim  ;  Jung-Nyoung Heo  ;  Hyun Cheol Chung  ;  Jiwon Choi  ;  Kyoung Tai No 
Citation
 BULLETIN OF THE KOREAN CHEMICAL SOCIETY, Vol.39(3) : 294-299, 2018 
Journal Title
 BULLETIN OF THE KOREAN CHEMICAL SOCIETY 
ISSN
 0253-2964 
Issue Date
2018
Keywords
Phosphatidylinositol 3-kinase beta ; Pharmacophore-based virtual screening ; Molecular dock-ing ; Molecular dynamics simulation ; Phosphatidylinositol 3-kinase beta inhibitors
Abstract
Phosphatidylinositol 3-kinase beta (PI3Kβ) is the dominant isoform of PI3K and has been implicated inthrombosis as well as phosphatase and tensin homologue-loss-induced tumorigenesis. PI3Kβhas beenconsidered to be an attractive target for anticancer drug discovery, and several PI3Kβinhibitors have pro-gressed into clinical trials. Here, we disclose the discovery of two natural products (PBY-0002 and PBY-0006) that have inhibitory effects on PI3Kβ. These two natural products were identified throughpharmacophore-based virtual screening, molecular docking, and a molecular dynamics simulation. Fur-thermore, anin vitroassay against human gastric cancer cell lines revealed that these two compoundsshowed anticancer activity. To identify the binding modes of PBY-0002 and PBY-0006 further, we per-formed a systematical investigation with comparison to the binding mode of GSK2636711, which is aknown PI3Kβinhibitor. The results demonstrated that PBY-0002 and PBY-0006 were tightly embeddedinto the ATP-binding site via hydrogen bonds andπ-cation interactions. These two natural products canprovide a promising starting point for the rational design of potent analogs with inhibitory activityagainst PI3Kβ.
DOI
10.1002/bkcs.11382
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kwon, Woo Sun(권우선)
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/175162
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