Application of chemical similarity and bioisosteres to find allosteric inhibitors of type 2 lipid kinase γ.

Phosphatidylinositol phosphate kinases (PIPKs) exist in three isoforms: I, II, and III. Some of these enzymes are promising drug targets for cancer, metabolic disorders, and neurodegenerative diseases. Type II PIPKs are notable for their dual roles, to perform phosphorylation reactions acting as lipid kinases and to carry out catalytic-independent functions. The dysregulation of Type II PIPKs is linked to several diseases, including psychiatric disorders, cancer, and infections. There is still a need to explore for strong inhibitors of these kinases. This study used a similarity search method to find analogs of the known PI5P4K2C inhibitor, DVF (5-methyl-2-(2-propan-2-ylphenyl)-N-(pyridin-2-ylmethyl)pyrrolo[3,2-d]pyrimidin-4-amine). It utilized open-access platforms like SwissSimilarity, SwissBioisosteres, and the STITCH database for the initial screening of molecules. Drug-likeness assessment of the selected molecules was followed by molecular docking and molecular dynamics simulations to evaluate their binding affinity and stability. Post-simulation analysis revealed four promising hit compounds, each containing a pyrrole-pyrimidine core, which exhibited superior binding free energies and interactions at the allosteric site compared to DVF. These findings highlight potential candidates for further development as PI5P4K2C inhibitors.