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@ARTICLE{WienenSchmidt:866049,
      author       = {Wienen-Schmidt, Barbara and Schmidt, Denis and Gerber,
                      Hans-Dieter and Heine, Andreas and Gohlke, Holger and Klebe,
                      Gerhard},
      title        = {{S}urprising {N}on-{A}dditivity of {M}ethyl-{G}roups in
                      {D}rug-{K}inase {I}nteraction},
      journal      = {ACS chemical biology},
      volume       = {14},
      number       = {12},
      issn         = {1554-8937},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {FZJ-2019-05295},
      pages        = {2585-2594},
      year         = {2019},
      abstract     = {Drug optimization is guided by biophysical methods with
                      increasing popularity. In the context of lead structure
                      modifications, the introduction of methyl groups is a simple
                      but potentially powerful approach. Hence, it is crucial to
                      systematically investigate the influence of ligand
                      methylation on biophysical characteristics such as
                      thermodynamics. Here, we investigate the influence of ligand
                      methylation in different positions and combinations on the
                      drug–kinase interaction. Binding modes and complex
                      structures were analyzed using protein crystallography.
                      Thermodynamic signatures were measured via isothermal
                      titration calorimetry (ITC). An extensive computational
                      analysis supported the understanding of the underlying
                      mechanisms. We found that not only position but also
                      stereochemistry of the methyl group has an influence on
                      binding potency as well as the thermodynamic signature of
                      ligand binding to the protein. Strikingly, the combination
                      of single methyl groups does not lead to additive effects.
                      In our case, the merger of two methyl groups in one ligand
                      leads to an entirely new alternative ligand binding mode in
                      the protein ligand complex. Moreover, the combination of the
                      two methyl groups also resulted in a nonadditive
                      thermodynamic profile of ligand binding. Molecular dynamics
                      (MD) simulations revealed distinguished characteristic
                      motions of the ligands in solution explaining the pronounced
                      thermodynamic changes. The unexpected drastic change in
                      protein ligand interaction highlights the importance of
                      crystallographic control even for minor modifications such
                      as the introduction of a methyl group. For an in-depth
                      understanding of ligand binding behavior, MD simulations
                      have shown to be a powerful tool.},
      cin          = {JSC / NIC / ICS-6},
      ddc          = {540},
      cid          = {I:(DE-Juel1)JSC-20090406 / I:(DE-Juel1)NIC-20090406 /
                      I:(DE-Juel1)ICS-6-20110106},
      pnm          = {511 - Computational Science and Mathematical Methods
                      (POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
      pid          = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:31638770},
      UT           = {WOS:000504806100012},
      doi          = {10.1021/acschembio.9b00476},
      url          = {https://juser.fz-juelich.de/record/866049},
}