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@ARTICLE{Ghaemi:820509,
      author       = {Ghaemi, Zhaleh and Alberga, Domenico and Carloni, Paolo and
                      Laio, Alessandro and Lattanzi, Gianluca},
      title        = {{P}ermeability {C}oefficients of {L}ipophilic {C}ompounds
                      {E}stimated by {C}omputer {S}imulations},
      journal      = {Journal of chemical theory and computation},
      volume       = {12},
      number       = {8},
      issn         = {1549-9626},
      address      = {Washington, DC},
      reportid     = {FZJ-2016-05802},
      pages        = {4093 - 4099},
      year         = {2016},
      abstract     = {The ability of a drug to cross the intestine–blood
                      barrier is a key quantity for drug design and employment and
                      is normally quantified by the permeability coefficient P,
                      often evaluated in the so-called Caco-2 assay. This assay is
                      based on measuring the initial growth rate of the
                      concentration of the drug beyond the cellular barrier but
                      not its steady-state flux through the membrane. This might
                      lead to confusion since, in the case of lipophilic drugs,
                      the initial slope is strongly affected by the retention of
                      the drug in the membrane. This effect is well known but
                      seldom considered in the assay. Here, we exploit all-atoms
                      molecular dynamics and bias exchange metadynamics to
                      calculate the concentration of two lipophilic drugs across a
                      model membrane as a function of time. This allows estimating
                      both the steady-state flux and the initial slope of the
                      concentration growth and comparing Caco-2 and steady-state
                      estimates of P. We show that our computational procedure is
                      able to reproduce the experimental values, although these
                      may differ from the permeability coefficients by orders of
                      magnitude. Our findings are generalized by a simplified
                      one-dimensional model of the permeation process that may act
                      as a roadmap to assess which measure of membrane
                      permeability would be more appropriate and, consequently,
                      whether retention corrections should be included in
                      estimates based on Caco-2 assays.},
      cin          = {IAS-5 / INM-9},
      ddc          = {540},
      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},
      UT           = {WOS:000381320200059},
      pubmed       = {pmid:27392273},
      doi          = {10.1021/acs.jctc.5b01126},
      url          = {https://juser.fz-juelich.de/record/820509},
}