Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Park H

PROVIDER: S-EPMC8003278 | biostudies-literature |

REPOSITORIES: biostudies-literature

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