Abstract
Human peptide deformylase (HsPDF) is an important target for anticancer drug discovery. In view of the limited HsPDF, inhibitors were reported, and high-throughput virtual screening (HTVS) studies based on HsPDF for developing new PDF inhibitors remain to be reported. We reported here on diverse small molecule inhibitors with excellent anticancer activities designed based on HTVS and molecular docking studies using the crystal structure of HsPDF. The compound M7594_0037 exhibited potent anticancer activities against HeLa, A549 and MCF-7 cell lines with IC50s of 35.26, 29.63 and 24.63 μM, respectively. Molecular docking studies suggested that M7594_0037 and its three derivatives could interact with HsPDF by several conserved hydrogen bonds. Moreover, the pharmacokinetic and toxicity properties of M7594_0037 and its derivatives were predicted using the OSIRIS property explorer. Thus, M7594_0037 and its derivatives might represent a promising scaffold for the further development of novel anticancer drugs.
Highlights
Peptide deformylase (PDF), a metalloenzyme containing Fe2+, is responsible for the removal of the N-formyl group from the terminal methionine residue in nascent proteins, which is essential to the synthesis of proteins [1,2]
HsPDF distributes over the mitochondrion in human cells, and functions to the PDF in pathogenic microorganisms, which catalyzes the deformylation of polypeptides [14,15,16,17]
The research on PDF as an antibacterial target was launched previously and a considerable sum of small molecular compounds have come into clinical trials
Summary
Peptide deformylase (PDF), a metalloenzyme containing Fe2+ , is responsible for the removal of the N-formyl group from the terminal methionine residue in nascent proteins, which is essential to the synthesis of proteins [1,2]. In the past few decades, peptide deformylase of pathogenic microorganisms has been considered as a potential target for antibacterial drug discovery, and plenty of PDF inhibitors have been widely reported [3,4,5,6,7]. Human genes of peptide deformylase (def ) have been cloned and expressed, and the resulting human peptide deformylase (HsPDF) has been studied extensively [1,11,12,13]. HsPDF distributes over the mitochondrion in human cells, and functions to the PDF in pathogenic microorganisms, which catalyzes the deformylation of polypeptides [14,15,16,17]. Inhibition of HsPDF results in mitochondrial membrane depolarization and promotes cell death [13,18]
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