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@ARTICLE{Robustelli:163399,
      author       = {Robustelli, Paul and Ibanez de Opakua, Alain and
                      Campbell-Bezat, Cecily and Giordanetto, Fabrizio and Becker,
                      Stefan and Zweckstetter, Markus and Pan, Albert C and Shaw,
                      David E},
      title        = {{M}olecular {B}asis of {S}mall-{M}olecule {B}inding to
                      α-{S}ynuclein.},
      journal      = {Journal of the American Chemical Society},
      volume       = {144},
      number       = {6},
      issn         = {1520-5126},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {DZNE-2022-00161},
      pages        = {2501 - 2510},
      year         = {2022},
      note         = {(CC BY-NC-ND)},
      abstract     = {Intrinsically disordered proteins (IDPs) are implicated in
                      many human diseases. They have generally not been amenable
                      to conventional structure-based drug design, however,
                      because their intrinsic conformational variability has
                      precluded an atomic-level understanding of their binding to
                      small molecules. Here we present long-time-scale,
                      atomic-level molecular dynamics (MD) simulations of
                      monomeric α-synuclein (an IDP whose aggregation is
                      associated with Parkinson's disease) binding the
                      small-molecule drug fasudil in which the observed
                      protein-ligand interactions were found to be in good
                      agreement with previously reported NMR chemical shift data.
                      In our simulations, fasudil, when bound, favored certain
                      charge-charge and π-stacking interactions near the C
                      terminus of α-synuclein but tended not to form these
                      interactions simultaneously, rather breaking one of these
                      interactions and forming another nearby (a mechanism we term
                      dynamic shuttling). Further simulations with small molecules
                      chosen to modify these interactions yielded binding
                      affinities and key structural features of binding consistent
                      with subsequent NMR experiments, suggesting the potential
                      for MD-based strategies to facilitate the rational design of
                      small molecules that bind with disordered proteins.},
      keywords     = {1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: analogs $\&$
                      derivatives / 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine:
                      chemistry / 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine:
                      metabolism / Amino Acid Sequence / Hydrogen Bonding /
                      Intrinsically Disordered Proteins: chemistry / Intrinsically
                      Disordered Proteins: metabolism / Ligands / Molecular
                      Conformation / Molecular Dynamics Simulation / Protein
                      Binding / Small Molecule Libraries: chemistry / Small
                      Molecule Libraries: metabolism / alpha-Synuclein: metabolism
                      / Intrinsically Disordered Proteins (NLM Chemicals) /
                      Ligands (NLM Chemicals) / Small Molecule Libraries (NLM
                      Chemicals) / alpha-Synuclein (NLM Chemicals) /
                      1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (NLM
                      Chemicals) / fasudil (NLM Chemicals)},
      cin          = {AG Zweckstetter},
      ddc          = {540},
      cid          = {I:(DE-2719)1410001},
      pnm          = {352 - Disease Mechanisms (POF4-352)},
      pid          = {G:(DE-HGF)POF4-352},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:35130691},
      pmc          = {pmc:PMC8855421},
      doi          = {10.1021/jacs.1c07591},
      url          = {https://pub.dzne.de/record/163399},
}