Structure-based virtual screening of FDA-approved drugs to discover potential inhibitors of phosphoinositide kinase, PIKfyve

The phosphoinositide kinase, PIKfyve is a lipid kinase that plays a vital role in membrane trafficking, endosomal transport, retroviral budding, and toll-like receptor signaling. Thus, it has emerged as a potential therapeutic target for several diseases, including, cancer, viral infections, and autoimmune diseases. However, a limited number of PIKfyve inhibitors have been reported so far. Herein, we report a structure-based virtual screening-driven identification of new PIKfyve inhibitors from a library of FDA-approved small molecule drugs. Labetalol, capsaicin and ibrutinib occupy the ATP pocket of PIKfyve with dock scores of -10.3, -10.6 and -12.24 kcal/mol, and MMGBSA binding energy of -57.3, -53.7 and -66.4 kcal/mol, respectively. These drugs inhibit PIKfyve with IC₅₀ values of 0.292, 0.965 and 0.678 µM, respectively, in an <i>in vitro</i> ADP-Glo kinase assay. Among the top hits from SBVS, labetalol as well as capsaicin display a stable interaction with the critical amino acid, LEU 119 of the hinge region during the 100 ns MD simulation. The results obtained herein warrant the exploration of these new inhibitors in preclinical disease models.