PDTD [Potential Drug Target Database]


The binding protein of the anti-Helicobacter pylori (H. pylori) natural product N-trans-caffeoyltyramin(1)

In a random screening of a diverse small molecules and herbal extracts library by using agar dilution method to identify active components against H. pylori, N-trans-caffeoyltyramineisolated from Ceratostigma willmottianum, a folk medicine used to remedy rheumatism, traumatic injury and parotitis, showed inhibitory activity against H. pylori. The PDTD was searched by the TarFisDock using N-trans-caffeoyltyramine (compound 1) as a probe. Homology search revealed that, among the fifteen candidates discovered by TarFisDock, only diaminopimelate decarboxylase (DC) and peptide deformylase (PDF) have homologous proteins in the genome of H. pylori. Enzymatic assay demonstrated compound 1 and its derivative (compound 2) are the potent inhibitors against the H. pylori PDF (HpPDF) with IC50 values of 10.8 and 1.25 µM, respectively. X-ray crystal structures of HpPDF and the complexes of HpPDF with 1 and 2 were determined for the first time, indicating that these two inhibitors bind well with the HpPDF binding pocket. All these indicate that HpPDF is a potential target for screening new anti-H. pylori agents.

Target identification

Figure 1. A schematic diagram for target identification by using reverse docking approach, TarFisDock, in conjunction with bioassay and structural biology.(a) Chemical structure of N-trans-caffeoyltyramine, a natural product isolated from the folk medicine Ceratostigma willmottianum. (b) A schematic representation of the in-house potential drug target database (PDTD). Other protein structure databases, like the PDB, can also be used for reverse docking.(c) Bioinformatic tools were used to search homology proteins of the target hits from the pathogenic genome. The homology proteins will be validated experimentally. (e) The target hits (HpDC and HpPDF) were expressed, and the binding affinities and/or inhibition or activation activities of the probes to the target hits were determined. In this way, the target candidates can be selected for further functional validation. (f) The crystal structure of natural product-target candidate (HpPDF) complex. This means that the binding between the natural product and target candidate was verified at the atomic level. The images of the proteins were generated using the PyMol program.


1. Cai, J., et al., Protein Sci, 2006. 15(9): p. 2071-81.