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Jinwon, Jeon
분자활성 촉매반응 연구단
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Structure-Based virtual screening and de novo design of PIM1 inhibitors with anticancer activity from natural products

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Title
Structure-Based virtual screening and de novo design of PIM1 inhibitors with anticancer activity from natural products
Author(s)
Hwangseo Park; Jinwon Jeon; Kewon Kim; Soyeon Choi; Sungwoo Hong
Publication Date
2021-03
Journal
Pharmaceuticals, v.14, no.3
Publisher
MDPI AG
Abstract
© 2021 by the authors.Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis. Methods: to identify effective PIM1 kinase inhibitors, structurebased virtual screening of natural products of plant origin and de novo design were carried out using the protein-ligand binding free energy function improved by introducing an adequate dehydration energy term. Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels. The results of extensive docking simulations showed that the inhibitory activity stemmed from the formation of multiple hydrogen bonds in combination with hydrophobic interactions in the ATP-binding site. Optimization of the biochemical potency by chemical modifications of the 2-benzylidenebenzofuran-3(2H)-one scaffold led to the discovery of several nanomolar inhibitors with antiproliferative activities against human breast cancer cell lines. Conclusions: these new PIM1 kinase inhibitors are anticipated to serve as a new starting point for the development of anticancer medicine.
URI
https://pr.ibs.re.kr/handle/8788114/9551
DOI
10.3390/ph14030275
ISSN
1424-8247
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > 1. Journal Papers (저널논문)
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