In silico screening of indinavir-based compounds targeting proteolytic activity in HIV PR: binding pocket fit approach

Abstract

The intense research on small molecule inhibitors of Human immunodeficiency virus (HIV)-protease (PR) has produced a diverse class of chemical scaffolds which includes clinically available HIV PR inhibitors (PRI). Till now, these inhibitors are insignificant for targeting proteolytic activity and few drug molecules on alterations can enhance the inhibition of PR enzyme. Here, we developed a method for screening of new hits from Cambridge structural database, based on binding mode of indinavir interaction participating atoms. Knowledge-based ligand screening technique approximately informs that new hits are also having same binding mode-like indinavir interaction patterns. Considering the importance of ligand fitting in binding pocket, we developed induced-fit models for each compound and we obtained accurate energy values in terms of binding and interaction energy. We found that newly search molecules are interacting better than known drug—indinavir and these new compounds are comparatively having better drug-like property. Finally, we demonstrated that pocket specific docking, energy utilization, interactions, and ADME for screened compounds are showing new hit compounds of indinavir are better HIV PRI and these new compounds can also show better activity in in vivo and in vitro conditions.