In Silico Designing of Peptidomimetics Enhancing Endoribonucleolytic Activities of Acinetobacter MazF Toxin as the Novel Anti-bacterial Candidates

Abstract

Acinetobacter infection is one of the main causes of mortality in the patients admitted to the intensive care units (ICUs). Activation of the MazF toxin in the Acinetobacter can be considered an effective antibacterial strategy against the pathogen. Like some antibiotics, the released MazF toxin from the MazF–MazE TA system is able to do a ribonucleolytic activity and dissociate of the bacterial DNA leading to the cell disruption. In this study, it was attempt to design the peptidomimetics that can target the Acinetobacter MazF–MazE interactions. The peptide sequence that was used to peptidomimetics designing was NWN and named the short peptide. The short peptide sequence was obtained from an original peptide sequence (NNWNN). By using both pharmacophore and shape similarity strategies, 200 peptidomimics were obtained. 58 of 200 mimetics agreed with the Lipinski’s rule of five (RO5). All drug-like peptidomimetics were docked against MazF using AutoDock Vina in PyRx 0.8. Free energy of interaction and the number of hydrogen bonds were used to obtain binding affinity of the receptor (MazF) and each mimetic. Docking of the MazF-original peptide (NNWNN) and MazF-short peptide (NWN) were performed as controls. Peptidomimtics that had more hydrogen bonds and lower free energies can have higher binding affinity to the receptor and be suitable drug candidates against Acinetobacter for the future evaluations. Among all designed mimetics, nine best-ranked mimetics were selected based on the ligand–receptor binding energy. The best-ranked mimetics showed higher binding energies to the receptor compared to the binding energies of the original peptide-receptor and short peptide-receptor. The mimetics 2, 3, 5, 6, 7 and 9 formed more hydrogen bonds with the receptor compared to the short peptide. None of the mimetics formed more hydrogen bonds with the receptor compared to the original peptide. Based on the binding mode to the receptor (hydrogen bonds), mimetics 2, 3, 5, 6, 7 and 9 may be the best lead compounds among the novel designed mimetics. The potential compounds can be evaluated in vitro and in vivo for their activity as well as the cytotoxicity.