Identification of LasR ligands through a virtual screening approach

TY - JOUR

T1 - Identification of LasR ligands through a virtual screening approach

AU - Skovstrup, Søren

AU - Le Quement, Sebastian Thordal

AU - Hansen, Thomas

AU - Jakobsen, Tim Holm

AU - Harmsen, Morten

AU - Tolker-Nielsen, Tim

AU - Nielsen, Thomas E

AU - Givskov, Michael

AU - Taboureau, Olivier

N1 - Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2013/1

Y1 - 2013/1

N2 - With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity.

AB - With the widespread occurrence of bacterial resistance to antibiotics, the development of new strategies beyond conventional treatments is a pursuit taken by public health institutions worldwide. LasR, a transcription factor that controls quorum sensing in Pseudomonas aeruginosa, has emerged as an attractive therapeutic target for the next generation of antimicrobial agents. In the present study, a virtual screening workflow combining pharmacophore- and structure-based approaches was used to identify new LasR ligands. Five novel inducers and three inhibitors of LasR activity were validated experimentally by use of a cell-based assay. Interestingly, these compounds are molecularly distinct from the native signal molecule, N-3-oxododecanoyl-L-homoserine lactone (OHN), and may serve as lead structures for the design of new drugs. The binding modes of these compounds to the OHN binding site in LasR were predicted and used to identify the key interactions that contribute to the induction and inhibition of LasR activity.

U2 - 10.1002/cmdc.201200434

DO - 10.1002/cmdc.201200434

M3 - Journal article

C2 - 23203920

SN - 1860-7179

VL - 8

SP - 157

EP - 163

JO - ChemMedChem

JF - ChemMedChem

IS - 1

ER -