In silico development of broad spectrum antibacterial by targeting peptide deformylase

Abstract

Peptide Deformylase (PDF) is an essential metalloenzyme and removes the formyl group from methionine at the N terminus of nascent polypeptide chains. Since this protein is essential for survival of most of the pathogenic bacteria and functionally equivalent gene is absent in mammalian cells, it provides an attractive target for development of novel antibacterials. In the current project, an In silico approach has been used to develop a novel broad spectrum antibacterial based on binding affinity of PDF with derivatives of hydrazines. Virtual screening and Molecular docking based on Lamarckian Genetic Algorithm was carried out to find binding affinity of PDFs from seven different pathogenic bacteria. These molecules were screened from PubChem database on the basis of structural similarity to sulfonylpiperidine. Molecular Dockings were carried out for each ligand and results were clustered together with accepted RMSD of 0.5 Ao. Hydrogen bond analysis was done on UCSF Chimera while ADME and toxicity properties were evaluated using Molsoft and PreADMET server. 1-(4-fluorophenyl) sulfonylpiperidine-3-carbohydrazide (CID_4539974) was found to be the best potent inhibitor of PDF, made H-bonds with active metal binding amino residues, successfully passed the Lipinski rule of five, gained good drug-likeness model score, and exhibited negative carcinogenicity and toxicity test. Further, molecular dynamics simulation (MDS) was done to check the stability of protein-ligand complex under using GROMACSv4.05. Negative system energies of protein-ligand complex, negligible deviation of Cá from crystal structure and decrease in fluctuations in region containing active metal binding amino acid residue supported the stability of protein-ligand complex. The outcomes concluded that CID_4539974 have all the desirable properties to become a novel broad spectrum antibacterial by targeting bacterial PDF efficiently that needs further validation by wet lab experiments.