Multistep virtual screening based identification of homeodomain-interacting protein kinase 2 inhibitors: An opportunity for treating Chronic Kidney Disease

Abstract

Homeodomain-Interacting Protein Kinase 2 (HIPK2) is a critical regulator of multiple pathways upstream of Chronic Kidney Disease (CKD). With the purpose of seeking HIPK2 inhibitors with novel scaffolds, a multistep virtual screening from the SPECS library was conducted. The screening process generally included similarity screening, random forest modeling, docking and ADMET prediction. Ten compounds were finally purchased and evaluated in biological activity test. The activity results demonstrated that the compound 1 (SPECS ID AG-401/37408043) can inhibit enzymatic activity and cell viability of high-glucose-induced rat normal renal interstitial fibroblast cells (NRK49F) with moderate activity. Its binding modes with the HIPK2 ATP binding site were analyzed. Overall, the compound 1 with a rather new scaffold might be used as the lead for the future structural optimization to seek potent HIPK2 inhibitors.