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@ARTICLE{Guaitoli:890311,
      author       = {Guaitoli, Valentina and Alvarez-Ginarte, Yoanna María and
                      Montero-Cabrera, Luis Alberto and Bencomo-Martínez, Alberto
                      and Badel, Yoana Pérez and Giorgetti, Alejandro and Suku,
                      Eda},
      title        = {{A} computational strategy to understand structure-activity
                      relationship of 1,3-disubstituted imidazole [1,5-α]
                      pyrazine derivatives described as {ATP} competitive
                      inhibitors of the {IGF}-1 receptor related to {E}wing
                      sarcoma},
      journal      = {Journal of molecular modeling},
      volume       = {26},
      number       = {8},
      issn         = {0948-5023},
      address      = {Heidelberg},
      publisher    = {Springer},
      reportid     = {FZJ-2021-00884},
      pages        = {222},
      year         = {2020},
      note         = {Unfortunately, the authors do not have a copy of the
                      submitted version anymore},
      abstract     = {We followed a comprehensive computational strategy to
                      understand and eventually predict the structure-activity
                      relationship ofthirty-three 1,3-disubstituted imidazole
                      [1,5-α] pyrazine derivatives described as ATP competitive
                      inhibitors of the IGF-1receptor related to Ewing sarcoma.
                      The quantitative structure-activity relationship model
                      showed that the inhibitory potency iscorrelated with the
                      molar volume, a steric descriptor and the net charge
                      calculated value on atom C1 (q1) and N4 (q4) of
                      thepharmacophore, all of them appearing to give a positive
                      contribution to the inhibitory activity. According to
                      experimental andcalculated values, the most potent
                      compoundwould be 3-[4-(azetidin-2-ylmethyl)
                      cyclohexyl]-1-[3-(benzyloxy) phenyl]
                      imidazo[1,5-α]pyrazin-8-amine (compound 23). Docking was
                      used to guess important residues involved in the
                      ATP-competitive inhibitoryactivity. It was validated by 200
                      ns of molecular dynamics (MD) simulation using improved
                      linear interaction energy (LIE)method. MD of previously
                      preferred structures by docking shows that the most potent
                      ligand could establish hydrogen bondswith the ATP-binding
                      site of the receptor, and the Ser979 and Ser1059 residues
                      contribute favourably to the binding stability ofcompound
                      23.MDsimulation also gave arguments about the chemical
                      structure of the compound 23 being able to fit in the
                      ATPbindingpocket, expecting to remain stable into it during
                      the entire simulation and allowing us to hint the
                      significant contributionexpected to be given by
                      electrostatic and hydrophobic interactions to the
                      ligand-receptor complex stability. This
                      computationalcombined strategy here described could
                      represent a useful and effective prime approach to guide the
                      identification of tyrosinekinase inhibitors as new lead
                      compounds.},
      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},
      pubmed       = {32748063},
      UT           = {WOS:000555990300001},
      doi          = {10.1007/s00894-020-04470-w},
      url          = {https://juser.fz-juelich.de/record/890311},
}