Accession Number : ADA601728


Title :   3-Substituted Indole Inhibitors Against Francisella tularensis FabI Identified by Structure-Based Virtual Screening


Descriptive Note : Journal article


Corporate Author : ARMY MEDICAL RESEARCH INST OF INFECTIOUS DISEASES FORT DETRICK MD


Personal Author(s) : Hu, Xin ; Compton, Jaimee R ; AbdulHameed, Mohamed D ; Marchand, Charles L ; Robertson, Kelly L ; Leary, Dagmar H ; Jadhav, Ajit ; Hershfield, Jeremy R ; Wallqvist, Anders ; Friedlander, Arthur M ; Legler, Patricia M


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/a601728.pdf


Report Date : 01 Jul 2013


Pagination or Media Count : 14


Abstract : In this study, we describe novel inhibitors against Francisella tularensis SchuS4 FabI identified from structure-based in silico screening with integrated molecular dynamics simulations to account for induced fit of a flexible loop crucial for inhibitor binding. Two 3-substituted indoles, 54 and 57, preferentially bound the NAD+ form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured Ki. While 57 was species-specific, 54 showed a broader spectrum of growth inhibition against F. tularensis, Bacillus anthracis, and Staphylococcus aureus. Binding interaction analysis in conjunction with site-directed mutagenesis revealed key residues and elements that contribute to inhibitor binding and species specificity. Mutation of Arg-96, a poorly conserved residue opposite the loop, was unexpectedly found to enhance inhibitor binding in the R96G and R96M variants. This residue may affect the stability and closure of the flexible loop to enhance inhibitor (or substrate) binding.


Descriptors :   *FRANCISCELLA TULARENSIS , ENZYME INHIBITORS , INDOLES


Subject Categories : Biochemistry
      Pharmacology


Distribution Statement : APPROVED FOR PUBLIC RELEASE