Prediction of the binding modes between BB-83698 and peptide deformylase from Bacillus stearothermophilus by docking and molecular dynamics simulation

BB-83698 is a first potent inhibitor of peptide deformylase in this novel class to enter clinical trials. In this study, automated docking, molecular dynamics simulation and binding free energy calculations with the linear interaction energy (LIE) method are first applied to investigate the binding of BB-83698 to the peptide deformylase from Bacillus stearothermophilus. The lowest docking energy structure from each cluster is selected as different representative binding modes. Compared with the experimental data, the results show that the binding of BB-83698 in Mode 1 is the most stable, with a binding free energy of − 41.35 kJ/mol. The average structure of the Mode 1 complex suggests that inhibitor interacts with Ile59 and Gly109 by hydrogen bond interaction and with Pro47, Pro57, Ile59 and Leu146 by hydrophobic interaction are essential for the activity of BB-83698. Mode 2 represents a new binding mode. Additionally, if the hydrophilic group is introduced to the benzo-[1,3]-dioxole ring, the binding affinity of BB-83698 to the peptide deformylase from B. stearothermophilus will be greatly improved.