[논문]Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products

Park, Hwangseo; Jeon, Jinwon; Kim, Kewon; Choi, Soyeon; Hong, Sungwoo

doi:10.3390/ph14030275

[해외논문] Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products 원문보기

Pharmaceuticals, v.14 no.3, 2021년, pp.275 -

Park, Hwangseo (Department of Bioscience and Biotechnology and Institute of Anticancer Medicine Development, Sejong University, 209 Neungdong-ro, Kwangjin-gu, Seoul 05006, Korea) , Jeon, Jinwon (Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea) , Kim, Kewon (chistar@kaist.ac.kr (J.J.)) , Choi, Soyeon (kkw105701@kaist.ac.kr (K.K.)) , Hong, Sungwoo (sychoi94@kaist.ac.kr (S.C.))

Abstract ▼ AI-Helper

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, structure-based 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.

Keyword

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