Derivatives of salicylic acid as inhibitors of YopH in yersinia pestis

Zunnan Huang, Yantao He, Xian Zhang, Andrea Gunawan, Li Wu, Zhong-Yin Zhang, Chung F. Wong

Research output: Contribution to journalArticle

25 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)85-99
Number of pages15
JournalChemical Biology and Drug Design
Volume76
Issue number2
DOIs
StatePublished - 2010

Fingerprint

Yersinia pestis
Salicylic Acid
Hydrocarbons
Biological Warfare Agents
Derivatives
Phosphotyrosine
Protein Tyrosine Phosphatases
Plague
Gastrointestinal Diseases
Structural Models
Catalytic Domain
Proteins
Crystal structure
Ligands
Pharmaceutical Preparations

Keywords

  • click chemistry
  • distance-dependent dielectric model
  • docking by simulated annealing
  • Generalized Born model
  • receiver operating characteristics curve
  • sensitivity and specificity of screening models

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Medicine(all)

Cite this

Derivatives of salicylic acid as inhibitors of YopH in yersinia pestis. / Huang, Zunnan; He, Yantao; Zhang, Xian; Gunawan, Andrea; Wu, Li; Zhang, Zhong-Yin; Wong, Chung F.

In: Chemical Biology and Drug Design, Vol. 76, No. 2, 2010, p. 85-99.

Research output: Contribution to journalArticle

Huang, Zunnan ; He, Yantao ; Zhang, Xian ; Gunawan, Andrea ; Wu, Li ; Zhang, Zhong-Yin ; Wong, Chung F. / Derivatives of salicylic acid as inhibitors of YopH in yersinia pestis. In: Chemical Biology and Drug Design. 2010 ; Vol. 76, No. 2. pp. 85-99.
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