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@ARTICLE{Casasnovas:829377,
      author       = {Casasnovas, Rodrigo and Limongelli, Vittorio and Tiwary,
                      Pratyush and Carloni, Paolo and Parrinello, Michele},
      title        = {{U}nbinding {K}inetics of a p38 {MAP} {K}inase {T}ype {II}
                      {I}nhibitor from {M}etadynamics {S}imulations},
      journal      = {Journal of the American Chemical Society},
      volume       = {139},
      number       = {13},
      issn         = {1520-5126},
      address      = {Washington, DC},
      publisher    = {American Chemical Society},
      reportid     = {FZJ-2017-03090},
      pages        = {4780 - 4788},
      year         = {2017},
      abstract     = {Understanding the structural and energetic requisites of
                      ligand binding toward its molecular target is of paramount
                      relevance in drug design. In recent years, atomistic free
                      energy calculations have proven to be a valid tool to
                      complement experiments in characterizing the thermodynamic
                      and kinetic properties of protein/ligand interaction. Here,
                      we investigate, through a recently developed
                      metadynamics-based protocol, the unbinding mechanism of an
                      inhibitor of the pharmacologically relevant target p38 MAP
                      kinase. We provide a thorough description of the ligand
                      unbinding pathway identifying the most stable binding mode
                      and other thermodynamically relevant poses. From our
                      simulations, we estimated the unbinding rate as koff = 0.020
                      ± 0.011 s–1. This is in good agreement with the
                      experimental value (koff = 0.14 s–1). Next, we developed a
                      Markov state model that allowed identifying the
                      rate-limiting step of the ligand unbinding process. Our
                      calculations further show that the solvation of the ligand
                      and that of the active site play crucial roles in the
                      unbinding process. This study paves the way to
                      investigations on the unbinding dynamics of more complex p38
                      inhibitors and other pharmacologically relevant inhibitors
                      in general, demonstrating that metadynamics can be a
                      powerful tool in designing new drugs with engineered
                      binding/unbinding kinetics.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {574 - Theory, modelling and simulation (POF3-574)},
      pid          = {G:(DE-HGF)POF3-574},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000398764000030},
      pubmed       = {pmid:28290199},
      doi          = {10.1021/jacs.6b12950},
      url          = {https://juser.fz-juelich.de/record/829377},
}