title: Derivatives of salicylic acid as inhibitors of YopH in Yersinia pestis.
abstract: Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site of the protein to achieve binding affinity and selectivity. One moiety possessed the salicylic acid core intending to target the phosphotyrosine-binding pocket. The other moiety contained different chemical fragments meant to target a nearby secondary pocket. The two series of compounds differed by having hydrocarbon linkers with different lengths. Before experimental co-crystal structures are available, we have performed molecular docking to predict how these compounds might bind to the protein and to generate structural models for performing binding affinity calculation to aid future optimization of these series of compounds.
authors.affiliation: Department of Chemistry and Biochemistry and Center for Nanoscience, University of Missouri-Saint Louis, One University Boulevard, St. Louis, MO 63121, USA.
authors.forename: Zunnan
authors.initials: Z
authors.lastname: Huang
authors.forename: Yantao
authors.initials: Y
authors.lastname: He
authors.forename: Xian
authors.initials: X
authors.lastname: Zhang
authors.forename: Andrea
authors.initials: A
authors.lastname: Gunawan
authors.forename: Li
authors.initials: L
authors.lastname: Wu
authors.forename: Zhong-Yin
authors.initials: ZY
authors.lastname: Zhang
authors.forename: Chung F
authors.initials: CF
authors.lastname: Wong
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001425:Bacterial Outer Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D017434:Protein Structure, Tertiary; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020156:Salicylic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D015010:Yersinia pestis / Q000201:enzymology*
chemical_list: D000900:Anti-Bacterial Agents; D001425:Bacterial Outer Membrane Proteins; D054852:Small Molecule Libraries; D017027:Protein Tyrosine Phosphatases; C067571:yopH protein, Yersinia; D020156:Salicylic Acid