Bioinformatics

Biography

Biography: Mahreen Arooj

Abstract

Off-target binding connotes the binding of a small molecule of therapeutic significance to a protein target in addition to the primary target for which it was proposed. Progressively such off-targeting is emerging to be regular practice to reveal side effects. Here,we have developed a robust computational strategy using structure-based systems biology approach that is applicable to any enzyme system and that allows the prediction of drug effects on biological processes. Chymase is an enzyme of hydrolase class that catalyzes hydrolysis of peptide bonds. A link between heart failure and chymase is ascribed, and a chymase inhibitor is in clinical phase II for treatment of heart failure. However, the underlying mechanisms of the off-target effects of human chymase inhibitors are still unclear. In this study, putative off-targets for huamn chymase inhibitors were identified through various structural and functional similarity analyses and molecular docking studies. Finally, literature survey along with KEGG pathway maps  was performed to incorporate these off-targets into biological pathways and to establish links between pathways and particular adverse effects. Off-targets of chymase inhibitors are linked to various biological pathways such as classical and lectin pathways of complement system, intrinsic and extrinsic pathways of coagulation cascade, and fibrinolytic system. Prospectively, our approach is helpful not only to better understand the mechanisms of chymase inhibitors but also for drug repurposing exercises to find novel uses for these inhibitors. This study also demonstrates the significance of computational strategies for efficacy prediction and the role that systems biology may play in multitarget therapeutics.