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

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• 作者：Xin Hu ; Jaimee R. Compton ; Mohamed Diwan M. AbdulHameed ; Charles L. Marchand ; Kelly L. Robertson ; Dagmar H. Leary ; Ajit Jadhav ; Jeremy R. Hershfield ; Anders Wallqvist ; Arthur M. Friedlander ; Patricia M. Legler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 11, 2013
• 年：2013
• 卷：56
• 期：13
• 页码：5275-5287
• 全文大小：638K
• 年卷期：v.56,no.13(July 11, 2013)
• ISSN：1520-4804

文摘

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, <b>54b> and <b>57b>, preferentially bound the NAD⁺ form of the enzyme and inhibited growth of F. tularensis SchuS4 at concentrations near that of their measured Kb>ib>. While <b>57b> was species-specific, <b>54b> 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.