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@ARTICLE{Bochicchio:280465,
      author       = {Bochicchio, Anna and Rossetti, Giulia and Tabarrini, Oriana
                      and Krauβ, Sybille and Carloni, Paolo},
      title        = {{M}olecular {V}iew of {L}igands {S}pecificity for {CAG}
                      {R}epeats in {A}nti-{H}untington {T}herapy},
      journal      = {Journal of chemical theory and computation},
      volume       = {11},
      number       = {10},
      issn         = {1549-9626},
      address      = {Washington, DC},
      publisher    = {American Chemical Society (ACS)},
      reportid     = {FZJ-2016-00239},
      pages        = {4911 - 4922},
      year         = {2015},
      abstract     = {Huntington’s disease is a fatal and devastating
                      neurodegenerative genetic disorder for which there is
                      currently no cure. It is characterized by Huntingtin
                      protein’s mRNA transcripts with 36 or more CAG repeats.
                      Inhibiting the formation of pathological complexes between
                      these expanded transcripts and target proteins may be a
                      valuable strategy against the disease. Yet, the rational
                      design of molecules specifically targeting the expanded CAG
                      repeats is limited by the lack of structural information.
                      Here, we use well-tempered metadynamics-based free energy
                      calculations to investigate pose and affinity of two ligands
                      targeting CAG repeats for which affinities have been
                      previously measured. The first consists of two
                      4-guanidinophenyl rings linked by an ester group. It is the
                      most potent ligand identified so far, with Kd = 60(30) nM.
                      The second consists of a 4-phenyl dihydroimidazole and
                      4–1H-indole dihydroimidazole connected by a C–C bond (Kd
                      = 700(80) nM). Our calculations reproduce the experimental
                      affinities and uncover the recognition pattern between
                      ligands’ and their RNA target. They also provide a
                      molecular basis for the markedly different affinity of the
                      two ligands for CAG repeats as observed experimentally.
                      These findings may pave the way for a structure-based
                      hit-to-lead optimization to further improve ligand
                      selectivity toward CAG repeat-containing mRNAs.},
      cin          = {JSC / IAS-5 / INM-9 / GRS Jülich ; German Research School
                      for Simulation Sciences},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)IAS-5-20120330 /
                      I:(DE-Juel1)INM-9-20140121 / I:(DE-Juel1)GRS-20100316},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / 572 - (Dys-)function and Plasticity (POF3-572)},
      pid          = {G:(DE-HGF)POF3-511 / G:(DE-HGF)POF3-572},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000362921700040},
      pubmed       = {pmid:26574279},
      doi          = {10.1021/acs.jctc.5b00208},
      url          = {https://juser.fz-juelich.de/record/280465},
}