A Lead-Based Fragment Library Screening of the Glycosyltransferase WaaG from Escherichia coli

Abstract

Glucosyl transferase I (WaaG) in E. coli catalyzes the transfer of an α-D-glucosyl group to the inner core of the lipopolysaccharide (LPS) and plays an important role in the biogenesis of the outer membrane. If its activity could be inhibited, the integrity of the outer membrane would be compromised and the bacterium would be susceptible to antibiotics that are normally prevented from entering the cell. Herein, three libraries of molecules (A, B and C) were docked in the binding pocket of WaaG, utilizing the docking binding affinity as a filter to select fragment-based compounds for further investigations. From the results of the docking procedure, a selection of compounds was investigated by molecular dynamics (MD) simulations to obtain binding free energy (BFE) and KD values for ligands as an evaluation for the binding to WaaG. Derivatives of 1,3-thia-zoles (A7 and A4) from library A and 1,3,4-thiadiazole (B33) from library B displayed a promising profile of BFE, with KD