title: Peptide deformylase is a potential target for anti-Helicobacter pylori drugs: reverse docking, enzymatic assay, and X-ray crystallography validation.
abstract: Colonization of human stomach by the bacterium Helicobacter pylori is a major causative factor for gastrointestinal illnesses and gastric cancer. However, the discovery of anti-H. pylori agents is a difficult task due to lack of mature protein targets. Therefore, identifying new molecular targets for developing new drugs against H. pylori is obviously necessary. In this study, the in-house potential drug target database (PDTD, http://www.dddc.ac.cn/tarfisdock/) was searched by the reverse docking approach using an active natural product (compound 1) discovered by anti-H. pylori screening as a probe. Homology search revealed that, among the 15 candidates discovered by reverse docking, 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 H. pylori PDF (HpPDF) with IC50 values of 10.8 and 1.25 microM, 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 HpPDF binding pocket. All these results indicate that HpPDF is a potential target for screening new anti-H. pylori agents. In addition, compounds 1 and 2 were predicted to bind to HpPDF with relatively high selectivity, suggesting they can be used as leads for developing new anti-H. pylori agents. The results demonstrated that our strategy, reverse docking in conjunction with bioassay and structural biology, is effective and can be used as a complementary approach of functional genomics and chemical biology in target identification.
authors.affiliation: Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica Graduate School of Chinese Academy of Sciences, China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Cai
authors.forename: Cong
authors.initials: C
authors.lastname: Han
authors.forename: Tiancen
authors.initials: T
authors.lastname: Hu
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Dalei
authors.initials: D
authors.lastname: Wu
authors.forename: Fangdao
authors.initials: F
authors.lastname: Wang
authors.forename: Yunqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
authors.forename: Kaixian
authors.initials: K
authors.lastname: Chen
authors.forename: Jianmin
authors.initials: J
authors.lastname: Yue
authors.forename: Xu
authors.initials: X
authors.lastname: Shen
authors.forename: Hualiang
authors.initials: H
authors.lastname: Jiang
mesh_terms: D000581:Amidohydrolases / Q000737:chemistry* / Q000235:genetics; D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray / Q000379:methods*; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship
chemical_list: D000581:Amidohydrolases; C084507:peptide deformylase