A comparative study of different docking methodologies to assess the protein–ligand interaction for the E. coli MurB enzyme

Abstract

We have investigated the active site of E. coli MurB using the Quantum Mechanics/Molecular Mechanics (QM/MM) methodology. The docking of three novel series of 4-thiazolidinone derivatives has been performed using two methods: rigid docking and flexible docking (Induced Fit Docking: IFD). The results have been compared to understand the conformational aspects of the enzyme. The docking results from rigid docking show that the ligands with highly negative ΔGbind have poor docking scores. In addition, the value of the regression coefficient (R) obtained on correlating the ΔGbind and the experimental pMIC values is insignificant. On keeping the protein flexible, there is a remarkable improvement in both the docking score and ΔGbind , along with a good value of R (0.64). Two important residues, Tyr254 and Try190 are found to be highly displaced during the flexible docking and hence their role in effective ligand binding has been confirmed. Thus, comparing the two methodologies, IFD has emerged as the more appropriate one for studying the E. coli MurB enzyme. To further substantiate the findings, MD studies over a time period of 20 ns have been performed on the IFD-LIII j and Rigid/XP-LIII j complexes and the results shows the former complex to be more stable, with lower average RMSD and higher average ΔGbind. Communicated by Ramaswamy H. Sarma