In silico development of broad spectrum antibacterial by targeting peptide deformylase (original) (raw)
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Virtual Screening Approach of Bacterial Peptide Deformylase Inhibitors Results in New Antibiotics
Molecular informatics, 2017
The increasing resistance of bacteria to antibacterial therapy poses an enormous health problem, it renders the development of new antibacterial agents with novel mechanism of action an urgent need. Peptide deformylase, a metalloenzyme which catalytically removes N-formyl group from N-terminal methionine of newly synthesized polypeptides, is an important target in antibacterial drug discovery. In this study, we report the structure-based virtual screening of ZINC database in order to discover potential hits as bacterial peptide deformylase enzyme inhibitors with more affinity as compared to GSK1322322, previously known inhibitor. After virtual screening, fifteen compounds of the top hits predicted were purchased and evaluated in vitro for their antibacterial activities against one Gram positive (Staphylococcus aureus) and three Gram negative (Escherichia coli, Pseudomonas aeruginosa and Klebsiella. pneumoniae) bacteria in different concentrations by disc diffusion method. Out of the...
Structural Basis for the Design of Antibiotics Targeting Peptide Deformylase
Biochemistry, 1999
While protein synthesis in bacteria begins with a formylated methionine, the formyl group of the nascent polypeptide is removed by peptide deformylase. Since eukaryotic protein synthesis does not involve formylation and deformylation at the N-terminus, there has been increasing interest in peptide deformylase as a potential target for antibacterial chemotherapy. Toward this end and to aid in the design of effective antibiotics targeting peptide deformylase, the structures of the protein-inhibitor complexes of both the cobalt and the zinc containing Escherichia coli peptide deformylase bound to the transitionstate analogue, (S)-2-O-(H-phosphonoxy)-L-caproyl-L-leucyl-p-nitroanilide (PCLNA), have been determined. The proteins for both deformylase-inhibitor complexes show basically the same fold as for the native enzyme. The PCLNA inhibitor adopts an extended conformation and fits nicely into a hydrophobic cavity located near the metal site. On the basis of these structures, guidelines for the design of high-affinity deformylase inhibitors are suggested. As our results show that the protein residues which interact with the PCLNA inhibitor are conserved over a wide variety of species, we suggest that antibiotics targeting deformylase could have wide applicability.
A unique peptide deformylase platform to rationally design and challenge novel active compounds
Scientific Reports, 2016
Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against ...
Journal of Clinical Medicine, 2018
Bacterial peptide deformylase (PDF) is an attractive target for developing novel inhibitors against several types of multidrug-resistant bacteria. The objective of the current study is to retrieve potential phytochemicals as prospective drugs against Staphylococcus aureus peptide deformylase (SaPDF). The current study focuses on applying ligand-based pharmacophore model (PharmL) and receptor-based pharmacophore (PharmR) approaches. Utilizing 20 known active compounds, pharmL was built and validated using Fischer’s randomization, test set method and the decoy set method. PharmR was generated from the knowledge imparted by the Interaction Generation protocol implemented on the Discovery Studio (DS) v4.5 and was validated using the decoy set that was employed for pharmL. The selection of pharmR was performed based upon the selectivity score and further utilizing the Pharmacophore Comparison module available on the DS. Subsequently, the validated pharmacophore models were escalated for ...
Borneo Journal of Pharmacy
Increasing antibiotic-resistant pathogenic bacteria is a severe problem in the world. Therefore, there is a need to identify new drugs from natural products and also new drug targets. Cladophora sp. is a marine organism which is known to have bioactive compounds and a potential antibacterial. On the other hand, Peptide Deformylase (PDf) may prove to be a novel drug target since it is crucial for native peptide functioning in most pathogenic bacteria. This study screens for PDf inhibition activity of compounds from Cladophora sp. using molecular docking approach and screening the binding affinity of bioactive compounds against the peptide receptor PDf using Pyrex Autodock Vina software. Docking results were stored and visualized using Biovia Discovery Studio and PyMOL ligand. Ligands were obtained from previous literature in PubChem, and receptor peptide PDf from pathogenic bacteria: Pseudomonas aeruginosa (PDB ID:1N5N), Escherichia coli (PDB ID:1BSK), Enterococcus faecium (PDB ID:3G...
Journal of Combinatorial Chemistry, 2000
Peptide deformylase catalyzes the removal of the N-terminal formyl group from nascent polypeptides during prokaryotic protein synthesis and maturation and is essential for bacterial survival. Its apparent absence from mammalian organisms makes it an attractive target for designing novel antibacterial agents. Based on the substrate specificity of peptide deformylase from Escherichia coli, a focused library of peptide thiols was synthesized on TentaGel resin using a disulfide linkage. Screening of the library against the purified deformylase was carried out in solution phase after the inhibitors were released from the resin with a reducing agent. A potent deformylase inhibitor was obtained from a 750-member library and was further optimized through rational modification into a low nanomolar inhibitor (K I) 15 nM against E. coli deformylase).
The Journal of antimicrobial chemotherapy, 2012
OBJECTIVES: Bacterial drug resistance is a worrying public health problem and there is an urgent need for research and development to provide new antibacterial molecules. Peptide deformylase (PDF) is now a well-described intracellular target selected for the design of a new antibiotic group, PDF inhibitors (PDFIs). The initial bacterial susceptibility to an inhibitor of a cytoplasmic target is directly associated with the diffusion of the compound through the membrane barrier of Gram-negative bacteria and with its cytosolic accumulation at the required concentration. METHODS: We have recently demonstrated that the activity of different PDFIs is strongly dependent on the accumulation of the active molecules by using permeabilizing agents, efflux inhibitors or efflux-mutated strains. In this work we assessed various combination protocols using different putative inhibitors (PDFIs, methionine aminopeptidase inhibitors etc.) to improve antibacterial activity against various resistant Gr...
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2016
Herein, we report the synthesis and screening of biphenyl tetrazole-thiazolidinediones 14(a-j) as bacterial Peptide deformylase (PDF) enzyme inhibitors. The compounds 14b (IC50 value=16.25μM), 14c (IC50 value=18.00μM) and 14h (IC50 value=17.25μM) had shown good PDF inhibition activity. The compounds 14b (MIC range=20.75-35.41μg/mL), 14c (MIC range=19.41-26.00μg/mL) and 14d (MIC range=8.41-8.58μg/mL) had also shown potent antibacterial activity when compared with standard ciprofloxacin (MIC range=25-50μg/mL). Thus, the active derivatives were not only potent PDF inhibitors but also efficient antibacterial agents. In order to gain more insight on the binding mode of the compounds with PDF enzyme, the synthesized compounds 14(a-j) were docked against PDF enzyme of E. coli and compounds exhibited good binding properties. The results suggest that this class of compounds have been potential for development and use in a future as antibacterial drugs.
Ligand-Induced Changes in the Structure and Dynamics of Escherichia coli Peptide Deformylase
Biochemistry, 2009
Peptide deformylase (PDF) is an enzyme that is responsible for removing the formyl group from nascently synthesized polypeptides in bacteria, attracting much attention as a potential target for novel antibacterial agents. Efforts to develop potent inhibitors of the enzyme have progressed based on classical medicinal chemistry, combinatorial chemistry, and structural approaches. Yet, the validity of PDF as an antibacterial target hangs, in part, on the ability of inhibitors to selectively target this enzyme in favor of structurally related metallohydrolases. We have used 15 N NMR spectroscopy and isothermal titration calorimetry to investigate the high-affinity interaction of EcPDF with actinonin, a naturally occurring potent EcPDF inhibitor. Backbone amide chemical shifts, residual dipolar couplings, hydrogen-deuterium exchange, and 15 N relaxation reveal structural and dynamic effects of ligand binding in the immediate vicinity of the ligand binding site as well as at remote sites. A comparison of the crystal structures of free and actinonin-bound EcPDF with the solution data suggests that most of the consequences of ligand binding on the protein are lost or obscured during crystallization. The results of these studies improve our understanding of the thermodynamic global minimum and have important implications for structure-based drug design. Peptide deformylase (PDF) is an essential and highly conserved enzyme that functions in protein maturation by removing the N-formyl group from the methionine of nascently synthesized polypeptides in bacteria, protists and eukaryotic organelles (1-9). Because protein translation in bacteria is initiated with N-formyl-methionine, PDF has emerged as a target of efforts to develop novel antibacterial agents (10-16). The extensively characterized enzyme from E. coli (EcPDF) exhibits some substrate selectivity in vitro (4,6,17-21); this property has guided the design of several effective substrate analog inhibitors (18-23). Current work seeks to identify compounds with broad-spectrum activity against bacterial PDF while avoiding inhibition of other cellular targets, including the recently identified human mitochondrial protein (7,9,24).