title: Exploring the Molecular Basis for Binding of Inhibitors by Threonyl-tRNA Synthetase from Brucella abortus: A Virtual Screening Study.
abstract: Targeting threonyl-tRNA synthetase (ThrRS) of Brucella abortus is a promising approach to developing small-molecule drugs against bovine brucellosis. Using the BLASTp algorithm, we identified ThrRS from Escherichia coli (EThrRS, PDB ID 1QF6), which is 51% identical to ThrRS from Brucella abortus (BaThrRS) at the amino acid sequence level. EThrRS was used as the template to construct a BaThrRS homology model which was optimized using molecular dynamics simulations. To determine the residues important for substrate ATP binding, we identified the ATP-binding regions of BaThrRS, docked ATP to the protein, and identified the residues whose side chains surrounded bound ATP. We then used the binding site of ATP to virtually screen for BaThrRS inhibitors and got seven leads. We further characterized the BaThrRS-binding site of the compound with the highest predicted inhibitory activity. Our results should facilitate future experimental effects to find novel drugs for use against bovine brucellosis.
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. liming01@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. liming01@caas.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Li
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. wenfang@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. wenfang@caas.cn.
authors.forename: Fang
authors.initials: F
authors.lastname: Wen
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. zhaoshengguo1984@163.com.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. zhaoshengguo1984@163.com.
authors.forename: Shengguo
authors.initials: S
authors.lastname: Zhao
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. woaisanzang@126.com.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. woaisanzang@126.com.
authors.forename: Pengpeng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. lisongli@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. lisongli@caas.cn.
authors.forename: Songli
authors.initials: S
authors.lastname: Li
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. zhangyangdong@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. zhangyangdong@caas.cn.
authors.forename: Yangdong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. zhengnan@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. zhengnan@caas.cn.|State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. zhengnan@caas.cn.
authors.forename: Nan
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Ministry of Agriculture Laboratory of Quality &amp; Safety Risk Assessment for Dairy Products (Beijing), Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. wangjiaqi@caas.cn.|Ministry of Agriculture-Milk and Dairy Product Inspection Center (Beijing), Beijing 100193, China. wangjiaqi@caas.cn.|State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China. wangjiaqi@caas.cn.
authors.forename: Jiaqi
authors.initials: J
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001665:Binding Sites; D002003:Brucella abortus / Q000201:enzymology*; D002007:Brucellosis, Bovine / Q000188:drug therapy / Q000382:microbiology; D002417:Cattle; D004791:Enzyme Inhibitors / Q000378:metabolism*; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D017386:Sequence Homology, Amino Acid; D013914:Threonine-tRNA Ligase / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D013914:Threonine-tRNA Ligase
keywords: bovine brucellosis; docking; homology modeling; molecular dynamics; virtual screening