Peptide Deformylase Enzyme Inhibitor Design, Synthesis And Biological Activity

The emergence of multi-drug resistant bacterial has created an urgent demand for new antibacterial agents with novel mechanisms of action and new structures. One of the new targets currently receiving widespread interest is peptide deformylase (PDF). PDF is an essential iron containing metallo-enzyme that catalyzes the removal of N-formyl group from the N-formyl methionine of ribosome synthesized nascent polypeptide. The absence of deformylase activity in mammal cells, coupled with the observation that the gene encoding PDF (def) is present in all sequenced pathogenic bacterial genomes, has made PDF an attractive target for antibacterial chemotherapy.The crystal structure complexes of PDF with inhibitors and the SAR researches have revealed the essential structure demands of a PDF inhibitor: â‘  a moiety capable of chelating the essential metal at the catalytic site; â‘¡ a hydrophobic side chain to fill the hydrophobic pocket at the S₁' site; â‘¢ two amide group; â‘£ some hydrophobic groups at the P₃' of the inhibitors.The binding modes of a series of PDF inhibitors were explored using molecular docking software (SYBYL7.0 and Autodock3.0) and new shallow pockets near the known active pocket were found. These pockets can accommodate side chain at the P₃' of inhibitors such as aromatic groups. which could enhance the binding affinity. Autodock results were in good agreement with the experimental values, which demonstrated a good linear relationship and the trend can indicate that the docking program produces reasonable binding modes.Many PDF inhibitors show poor pharmacokinetics and selectivity due to their apparent peptide characteristics. Our strategy was to substitute the C-terminal amide bond of the lead compound actinonin with some heterocycles that would be hydrolytically stable and at the same time retain all the important protein binding interactions. Isoxazole. benzimidazole. oxazole and imidazole were chose to be incorporated into the newly designed inhibitors. Good binding mode was demonstrated using the docking procedure for most of the newly designed compounds.