Abstract
Peptide deformylase (PDF) is a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, which makes it an important antibacterial drug target. Given the importance of PDF inhibitors like actinonin in antibacterial drug discovery, several reported potent PDF inhibitors were used to develop pharmacophore models using the Galahad module of Sybyl 7.1 software. Generated pharmacophore models were composed of two donor atom centers, four acceptor atom centers and two hydrophobic groups. Model-1 was screened against the Zinc database and several compounds were retrieved as hits. Compounds with Qfit values of more than 60 were employed to perform a molecular docking study with the receptor Escherichia coli PDF, then compounds with docking score values of more than 6 were used to predict the in silico pharmacokinetic and toxicity risk via OSIRIS property explorer. Two known PDF inhibitors were also used to perform a molecular docking study with E. coli PDF as reference molecules. The results of the molecular docking study were validated by reproducing the crystal structure of actinonin. Molecular docking and in silico pharmacokinetic and toxicity prediction studies suggested that ZINC08740166 has a relatively high docking score of 7.44 and a drug score of 0.78.
Highlights
In this day and age, in spite of the rapid development of antibacterial drugs [1,2,3], infectious diseases remain the second-leading cause of death worldwide [4,5]
Based on previous studies [4], a series of peptide deformylase (PDF) inhibitors were obtained from the Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) and used for the generation of pharmacophore models
The generation of pharmacophore models, high-throughput virtual screening and molecular docking studies were performed in Sybyl 7.1
Summary
In this day and age, in spite of the rapid development of antibacterial drugs [1,2,3], infectious diseases remain the second-leading cause of death worldwide [4,5]. Many of these agents share the same targets, and the actual number of antibacterial targets is very limited [6], more and more bacteria have developed resistance to medicines used for treatment of human infections [4,7]. It is a major concern that we should search for new antibacterial agents with a high potency against drug-resistant pathogens. The target should be part of an essential pathway in the pathogens and be absent in human cells [4]. The recent research has confirmed that peptide deformylase (PDF) is a possible target to develop new antibacterial drugs [8,9]. PDF is an essential bacterial metalloenzyme, which deformylates the N-formylmethionine of newly synthesized polypeptides [10,11].
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