Identification of Novel Scaffold for PIM1 Kinase Inhibition by Ligand Based Virtual Screening

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Prostate cancer afflicts one in six men during their lifetime making this disease the second leading cause of cancer‐related deaths in men in the United States. Given the high prevalence of prostate cancer and the high failure rate of current prostate cancer therapies, development of new therapies for aggressive prostate cancer is a high priority. PIM1 kinase represent as a potential therapeutic target for prostate cancer drug development because they are overexpressed in prostate cancers. There are several PIM kinase inhibitors that have reached to clinical trials and search for the novel PIM1 kinase inhibitor has dramatically accelerated. In silico ligand based virtual high throughput screening is one of the most successful and efficient methods to screen millions of lead like molecules and discover potent lead molecule with novel scaffolds. The present study aim to identify novel scaffolds for selective inhibition of PIM1 kinase by ligand based screening of lead like 4,591,276 compounds from zinc database. A ligand query model with pharmacophore features using vROCS tool was generated by taking a set of well‐known PIM 1 kinase inhibitors. The model was then utilized to screen 4.6 million lead like molecules of ZINC database. The resulted hits were prioritized and purchased 24 compounds from Enamine and Chembridge screening libraries to screen for PIMI kinase inhibitory activity. The PIMI kinase inhibitory activity was performed for all the purchased compounds by using CycLex PIMI kinase assay. The results are displayed in figure 1. The compounds 7, 22, and 23 showed more than 40% inhibition. The best hit molecule identified by ligand based virtual screening is compound 23.Support or Funding InformationThis study was made possible, in part, by Molecular Biology research infrastructure support from grant number 2G12MD007605 from the NIMHD/NIH. We thank the Openeye Inc. for providing the academic license to use the virtual screening tools.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.