Structure-based virtual screening of LsrK kinase inhibitors to target quorum sensing

Prasanthi Medarametla, Viviana Gatta, Tommi Antero Kajander, Tuomo Laitinen, Päivi Sirpa Marjaana Tammela, Antti Poso

Research output: Contribution to journalArticleScientificpeer-review

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.
Original languageEnglish
JournalChemMedChem : chemistry enabling drug discovery.
Volume13
Issue number22
Pages (from-to)2400-2407
Number of pages8
ISSN1860-7179
DOIs
Publication statusPublished - 20 Nov 2018
MoE publication typeA1 Journal article-refereed

Fields of Science

  • 116 Chemical sciences
  • 317 Pharmacy
  • antibacterial agents
  • homology modeling
  • LsrK kinase
  • quorum sensing
  • virtual screening
  • AL-2
  • AUTOINDUCER-2
  • ASSAY
  • antibacterial agents
  • homology modeling
  • LsrK kinase
  • quorum sensing
  • virtual screening
  • AL-2
  • AUTOINDUCER-2
  • ASSAY

Cite this

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title = "Structure-based virtual screening of LsrK kinase inhibitors to target quorum sensing",
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.",
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author = "Prasanthi Medarametla and Viviana Gatta and Kajander, {Tommi Antero} and Tuomo Laitinen and Tammela, {P{\"a}ivi Sirpa Marjaana} and Antti Poso",
year = "2018",
month = "11",
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doi = "10.1002/cmdc.201800548",
language = "English",
volume = "13",
pages = "2400--2407",
journal = "ChemMedChem : chemistry enabling drug discovery.",
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Structure-based virtual screening of LsrK kinase inhibitors to target quorum sensing. / Medarametla, Prasanthi; Gatta, Viviana; Kajander, Tommi Antero; Laitinen, Tuomo; Tammela, Päivi Sirpa Marjaana; Poso, Antti.

In: ChemMedChem : chemistry enabling drug discovery., Vol. 13, No. 22, 20.11.2018, p. 2400-2407.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Structure-based virtual screening of LsrK kinase inhibitors to target quorum sensing

AU - Medarametla, Prasanthi

AU - Gatta, Viviana

AU - Kajander, Tommi Antero

AU - Laitinen, Tuomo

AU - Tammela, Päivi Sirpa Marjaana

AU - Poso, Antti

PY - 2018/11/20

Y1 - 2018/11/20

N2 - 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.

AB - 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.

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