Computational validation of inhibitors for human phosphatidylinositol 4-phosphate 5-kinase-type 1 α protein...

The phosphoinositides are a family of phospholipids produced by the action of phosphatidylinositol phosphate kinases (PIPKs) that perform sequential phosphorylation of inositol. One of these lipid kinases, phosphatidylinositol 4-phosphate 5-kinase type 1 α (PIP5K1α) generates phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2), important in cell signaling. PIP5K1α is implicated in cancer progression and therefore necessitates the discovery of its potent inhibitors. Screening of protein kinase inhibitors from BindingDB was performed for the human PIP5K1α (hPIP5K1α) AlphaFold model to gain insights into important structural features. ATP binding site was used for screening of protein kinase inhibitors. ISA-2011B, a specific inhibitor against hPIP5K1α was used as reference molecule. The hit molecules were analysed for their binding affinity, drug-likeness, carcinogenicity and stability through molecular docking, SwissADME, CarcinoPred-EL, and molecular dynamics (MD) simulations studies. Four protein kinase inhibitors, R547, GDC-0879, JNJ-7706621 and ABT-869 were found to bind hPIP5K1α via a stable complex formation. Lys194 in the N-terminal lobe, two hinge region residues Asn245 and Leu247, and Asp404 that precedes the activation loop in the C-terminal lobe make hydrogen bonding interactions with hit molecules. Major fluctuations are seen in the activation loop and two insertion regions in the C-terminal lobe. ISA-2011B and hit molecules; R547 and GDC-0879 display lower overall structural motion from PCA studies indicating stability of the conformational states during MD simulations. The hit molecules display favorable ADME properties and are predicted to be non-carcinogenic. The hit molecules in particular R547, have better binding free energies compared to reference molecule, ISA-2011B.