Structure-Based Development of New and Potent Inhibitors of PIM Kinases: A Computational Study.

The PIM kinases are a family of serine/threonine kinases that catalyze the ATP dependent phosphorylation. These kinases were identified to be overexpressed in a variety of malignancies and tumors and hence can be taken a therapeutic drug target. Pharmacophore-based virtual screening, were employed to identify lead compounds for PIM kinases. A seven featured pharmacophore model was developed on the basis of tricyclic benzothienopyrimidinone, a triple inhibitor of PIM kinases. The validated pharmacophore model was used to screen ZINC database. As a result, 1028 compounds were mapped on the pharmacophore model. These initial hits, were subjected to filtering via Lipinski's rule of five to predict drug like molecules. 1028 drug like hits were selected for evaluation using docking simulation. Finally, 22 hits having different structural properties and binding modes with all the three PIM kinases were selected as lead candidates for triple inhibitors. These candidates having different scaffolds have a strong likelihood to act as further starting points in the development of new and potential PIM kinases inhibitors. [ABSTRACT FROM AUTHOR]