Structure-Based Virtual Screening of LsrK Kinase Inhibitors to Target Quorum Sensing

ChemMedChem. 2018 Nov 20;13(22):2400-2407. doi: 10.1002/cmdc.201800548. Epub 2018 Oct 30.

Abstract

In the era of increased antibiotic resistance, targeting enzymes involved in bacterial communication (quorum sensing) represents a new strategy to fight bacterial infections. LsrK is a kinase responsible for the phosphorylation of autoinducer-2, a signaling molecule involved in quorum sensing. Inhibiting LsrK would lead to quorum sensing inactivation and interfere with the pathogenesis. In this study, we built the first LsrK 3D model and performed virtual screening of a locally available database. Selected compounds were tested against LsrK, and the analogue search conducted based on the positive hits led to the identification of low-micromolar LsrK inhibitors. These results prove the utility of the model and provide the first class of LsrK inhibitors to be further optimized as antivirulence agents.

Keywords: LsrK kinase; antibacterial agents; homology modeling; quorum sensing; virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bacterial Proteins / chemistry
  • Bacterial Proteins / genetics
  • Catalytic Domain
  • Chromobacterium / enzymology
  • Databases, Chemical
  • Drug Evaluation, Preclinical
  • Enzyme Assays
  • Escherichia coli / enzymology
  • Escherichia coli / genetics
  • Molecular Structure
  • Organic Chemicals / chemistry*
  • Protein Conformation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinases / chemistry
  • Protein Kinases / genetics
  • Quorum Sensing / drug effects*
  • Salmonella typhimurium / enzymology
  • Structure-Activity Relationship

Substances

  • Bacterial Proteins
  • Organic Chemicals
  • Protein Kinase Inhibitors
  • Protein Kinases