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@ARTICLE{Schmitz:1025644,
      author       = {Schmitz, Birte and Frieg, Benedikt and Homeyer, Nadine and
                      Jessen, Gisela and Gohlke, Holger},
      title        = {{E}xtracting binding energies and binding modes from
                      biomolecular simulations of fragment binding to
                      endothiapepsin},
      journal      = {Archiv der Pharmazie},
      volume       = {357},
      number       = {5},
      issn         = {0342-9385},
      address      = {Weinheim},
      publisher    = {Wiley-VCH},
      reportid     = {FZJ-2024-03033},
      pages        = {e2300612},
      year         = {2024},
      abstract     = {Fragment-based drug discovery (FBDD) aims to discover a set
                      of small binding fragments that may be subsequently linked
                      together. Therefore, in-depth knowledge of the individual
                      fragments' structural and energetic binding properties is
                      essential. In addition to experimental techniques, the
                      direct simulation of fragment binding by molecular dynamics
                      (MD) simulations became popular to characterize fragment
                      binding. However, former studies showed that long simulation
                      times and high computational demands per fragment are
                      needed, which limits applicability in FBDD. Here, we
                      performed short, unbiased MD simulations of direct fragment
                      binding to endothiapepsin, a well-characterized model system
                      of pepsin-like aspartic proteases. To evaluate the strengths
                      and limitations of short MD simulations for the structural
                      and energetic characterization of fragment binding, we
                      predicted the fragments' absolute free energies and binding
                      poses based on the direct simulations of fragment binding
                      and compared the predictions to experimental data. The
                      predicted absolute free energies are in fair agreement with
                      the experiment. Combining the MD data with binding mode
                      predictions from molecular docking approaches helped to
                      correctly identify the most promising fragments for further
                      chemical optimization. Importantly, all computations and
                      predictions were done within 5 days, suggesting that MD
                      simulations may become a viable tool in FBDD projects.},
      cin          = {IBG-4 / JSC / NIC / IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBG-4-20200403 / I:(DE-Juel1)JSC-20090406 /
                      I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5111 - Domain-Specific Simulation $\&$ Data Life Cycle Labs
                      (SDLs) and Research Groups (POF4-511) / 2171 - Biological
                      and environmental resources for sustainable use (POF4-217) /
                      GRK 2158 - GRK 2158: Naturstoffe und Analoga gegen
                      Therapie-resistente Tumoren und Mikroorganismen: Neue
                      Leitstrukturen und Wirkmechanismen (270650915)},
      pid          = {G:(DE-HGF)POF4-5111 / G:(DE-HGF)POF4-2171 /
                      G:(GEPRIS)270650915},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {38319801},
      UT           = {WOS:001158265900001},
      doi          = {10.1002/ardp.202300612},
      url          = {https://juser.fz-juelich.de/record/1025644},
}