Docking-based virtual screening and molecular dynamic studies to identify new RIOK2 inhibitors

Since RIO (right open reading frame) family of kinases including RIOK1, RIOK2 and RIOK3 do not have any domain similar to typical kinases, they have called atypical kinase. Role of RIO kinases in pre-rRNA processing has been demonstrated. Furthermore, various investigations have revealed the role of RIOK2 in the carcinogenesis and potential of RIOK2 inhibitors as anticancer medicine. In this study, an in-silico approach have been utilized to find potential RIOK2 inhibitors. A database of already approved drugs including more than 5000 ligands have been retrieved from ZINC database and virtually screened against RIOK2 as target protein using AutoDock Vina software. The study have been followed by drug likeness and pharmacokinetic properties prediction, semiflexible docking and molecular dynamic simulations of the top-docked ligands. Top-docked ligands have shown appropriate drug likeness and pharmacokinetic properties. Investigation of ligand-protein interactions after semiflexible docking have revealed that there are hydrogen bonds and hydrophobic interactions between the selected compounds and amino acids in the active site of RIOK2. Molecular dynamic simulations on the complexes of conivaptan and 4-hydroxy-estazolam as the best compounds, with RIOK2 have demonstrated stable protein-ligand interactions and have validated virtual screening and docking studies. Overall, the present study have been identified conivaptan and 4-hydroxy-estazolam as potential chemotherapeutic agent through inhibition of RIOK2.