Structural systems pharmacology: A framework for integrating metabolic network and structure-based virtual screening for drug discovery against bacteria.

Advances in genome-scale metabolic models (GEMs) and computational drug discovery have caused the identification of drug targets at the system-level and inhibitors to combat bacterial infection and drug resistance. Here we report a structural systems pharmacology framework that integrates the GEM and structure-based virtual screening (SBVS) method to identify drugs effective for Escherichia coli infection. The most complete genome-scale metabolic reconstruction integrated with protein structures (GEM-PRO) of E. coli, iML1515_GP, and FDA-approved drugs have been used. FBA was performed to predict drug targets in silico. The 195 essential genes were predicted in the rich medium. The subsystems in which a significant number of these genes are involved are cofactor, lipopolysaccharide (LPS) biosynthesis that are necessary for cell growth. Therefore, some proteins encoded by these genes are responsible for the biosynthesis and transport of LPS which is the first line of defense against threats. So, these proteins can be potential drug targets. The enzymes with experimental structure and cognate ligands were selected as final drug targets for performing the SBVS method. Finally, we have suggested those drugs that have good interaction with the selected proteins as drug repositioning cases. Also, the suggested molecules could be promising lead compounds. This framework may be helpful to fill the gap between genomics and drug discovery. Results show this framework suggests novel antibacterials that can be subjected to experimental testing soon and it can be suitable for other pathogens.