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Discovery of novel inhibitors of bacterial MurD and MurE ligases by structure-based virtual screening approach
Perdih, Andrej, farmacevt ; Šolmajer, Tomaž
The growing occurrence ofbacterial resistance to most of the available antibiotics has underlined an urgent need for the discovery of novel efficacious antibacterial agents. The biosynthesis of the ...bacterial peptidoglycan represents a collection ofhighly selective unexploited targets for novel antibacterial drug design. . In the peptidoglycan biosynthetic pathway MurD (UDP-N-acetylmuramoyl-l-alanine:d-glutamate ligase), a three domain bacterial protein, catalyses a highly specific incorporation ofthe d-glutamate to the cytoplasmic intermediate UDP-N-acetyl-muramoyl-l-alanine(UMA)utilizingATPhydrolysistoADPand Pi.Thepresenceof"open" conformations of the MurD enzyme suggests that binding of the ligands UMA and ATP is accompanied by the closure of the Cterminaldomainto thecatalyticallyactive"closedform"makingit a highlycomplexdynamictarget.1In addition, its proposed sequential enzymatic mechanism was corroborated by structural, biochemical and recentlycomputational studies.2'Structural studies of the N-sulfonyl-glutamic acid inhibitors of MurD3enabled the possibility of examining the binding modesof this class of compounds providing valuable information to the lead optimization phase of the drug discovery cycle.4 Based on the available information structure-based pharmacophore approach was utilized to identify the threeqimensionalchemical features necessary for the optimal molecular recognition. The derived 3D pharmacophoreswere subjected to a validation procedure using a set of active and inactive compounds. In conjunction with molecular interaction field calculations, determining energetically favourablebinding areas within the MurD binding site and molecular docking simulations, a virtual screening campaignwas performed resulting in the discovery of severalMurD enzyme inhibitors5.6
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