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. 2016 Jul 15;17(7):1141.
doi: 10.3390/ijms17071141.

Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs

Jian Gao  1   2 , Li Liang  3 , Yasheng Zhu  4 , Shengzhi Qiu  5 , Tao Wang  6 , Ling Zhang  7
Affiliations

Ligand and Structure-Based Approaches for the Identification of Peptide Deformylase Inhibitors as Antibacterial Drugs

Jian Gao et al. Int J Mol Sci. .

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.

Keywords: antibacterial drug; high-throughput virtual screening; molecular docking; peptide deformylase; pharmacophore model.

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Figures

Figure 1
Figure 1
Proposed general structure for peptide deformylase (PDF) inhibitor.
Figure 2
Figure 2
Obtained pharmacophore model consisting of two donor atom centers (DA), four acceptor atom centers (AA) and two hydrophobic groups (HY).
Figure 3
Figure 3
(a) Superposition of the crystal structure of Escherichia coli PDF-actinonin (colored in green) and its docked conformation (colored in yellow). The binding mode of three compounds in the E. coli PDF binding pocket: (b) ZINC12660672; (c) ZINC12652500 and (d) ZINC08740166. The red color bonds indicate the hydrogen bonds between compound and amino acids (colored by yellow).
Figure 4
Figure 4
Structures of retrieved hits from the Zinc database with docking score values of more than 6.
Figure 5
Figure 5
Chemical structures of known PDF inhibitors used for the generation of pharmacophore models.
See this image and copyright information in PMC

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