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@ARTICLE{FrancoUlloa:844311,
      author       = {Franco-Ulloa, Sebastian and La Sala, Giuseppina and
                      Miscione, Gian and De Vivo, Marco},
      title        = {{N}ovel {B}acterial {T}opoisomerase {I}nhibitors {E}xploit
                      {A}sp83 and the {I}ntrinsic {F}lexibility of the {DNA}
                      {G}yrase {B}inding {S}ite},
      journal      = {International journal of molecular sciences},
      volume       = {19},
      number       = {2},
      issn         = {1422-0067},
      address      = {Basel},
      publisher    = {Molecular Diversity Preservation International},
      reportid     = {FZJ-2018-01744},
      pages        = {453 -},
      year         = {2018},
      abstract     = {DNA gyrases are enzymes that control the topology of DNA in
                      bacteria cells. This is a vital function for bacteria. For
                      this reason, DNA gyrases are targeted by widely used
                      antibiotics such as quinolones. Recently, structural and
                      biochemical investigations identified a new class of DNA
                      gyrase inhibitors called NBTIs (i.e., novel bacterial
                      topoisomerase inhibitors). NBTIs are particularly promising
                      because they are active against multi-drug resistant
                      bacteria, an alarming clinical issue. Structural data
                      recently demonstrated that these NBTIs bind tightly to a
                      newly identified pocket at the dimer interface of the
                      DNA–protein complex. In the present study, we used
                      molecular dynamics (MD) simulations and docking calculations
                      to shed new light on the binding of NBTIs to this site.
                      Interestingly, our MD simulations demonstrate the intrinsic
                      flexibility of this binding site, which allows the pocket to
                      adapt its conformation and form optimal interactions with
                      the ligand. In particular, we examined two ligands, AM8085
                      and AM8191, which induced a repositioning of a key aspartate
                      (Asp83B), whose side chain can rotate within the binding
                      site. The conformational rearrangement of Asp83B allows the
                      formation of a newly identified H-bond interaction with an
                      NH on the bound NBTI, which seems important for the binding
                      of NBTIs having such functionality. We validated these
                      findings through docking calculations using an extended set
                      of cognate oxabicyclooctane-linked NBTIs derivatives (~150,
                      in total), screened against multiple target conformations.
                      The newly identified H-bond interaction significantly
                      improves the docking enrichment. These insights could be
                      helpful for future virtual screening campaigns against DNA
                      gyrase},
      cin          = {IAS-5 / INM-9},
      ddc          = {570},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {899 - ohne Topic (POF3-899)},
      pid          = {G:(DE-HGF)POF3-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29401640},
      UT           = {WOS:000427527400137},
      doi          = {10.3390/ijms19020453},
      url          = {https://juser.fz-juelich.de/record/844311},
}