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@ARTICLE{Gossen:891037,
      author       = {Gossen, Jonas and Albani, Simone and Hanke, Anton and
                      Joseph, Benjamin P. and Bergh, Cathrine and Kuzikov, Maria
                      and Costanzi, Elisa and Manelfi, Candida and Storici, Paola
                      and Gribbon, Philip and Beccari, Andrea R. and Talarico,
                      Carmine and Spyrakis, Francesca and Lindahl, Erik and
                      Zaliani, Andrea and Carloni, Paolo and Wade, Rebecca C. and
                      Musiani, Francesco and Kokh, Daria B. and Rossetti, Giulia},
      title        = {{A} {B}lueprint for {H}igh {A}ffinity {SARS}-{C}o{V}-2
                      {M}pro {I}nhibitors from {A}ctivity-{B}ased {C}ompound
                      {L}ibrary {S}creening {G}uided by {A}nalysis of {P}rotein
                      {D}ynamics},
      journal      = {ACS pharmacology $\&$ translational science},
      volume       = {4},
      number       = {3},
      issn         = {2575-9108},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {FZJ-2021-01324},
      pages        = {1079–1095},
      year         = {2021},
      abstract     = {The SARS-CoV-2 coronavirus outbreak continues to spread at
                      a rapid rate worldwide. The main protease (Mpro) is an
                      attractive target for anti-COVID-19 agents. Unexpected
                      difficulties have been encountered in the design of specific
                      inhibitors. Here, by analyzing an ensemble of ∼30 000
                      SARS-CoV-2 Mpro conformations from crystallographic studies
                      and molecular simulations, we show that small structural
                      variations in the binding site dramatically impact ligand
                      binding properties. Hence, traditional druggability indices
                      fail to adequately discriminate between highly and poorly
                      druggable conformations of the binding site. By performing
                      ∼200 virtual screenings of compound libraries on selected
                      protein structures, we redefine the protein’s druggability
                      as the consensus chemical space arising from the multiple
                      conformations of the binding site formed upon ligand
                      binding. This procedure revealed a unique SARS-CoV-2 Mpro
                      blueprint that led to a definition of a specific
                      structure-based pharmacophore. The latter explains the poor
                      transferability of potent SARS-CoV Mpro inhibitors to
                      SARS-CoV-2 Mpro, despite the identical sequences of the
                      active sites. Importantly, application of the pharmacophore
                      predicted novel high affinity inhibitors of SARS-CoV-2 Mpro,
                      that were validated by in vitro assays performed here and by
                      a newly solved X-ray crystal structure. These results
                      provide a strong basis for effective rational drug design
                      campaigns against SARS-CoV-2 Mpro and a new computational
                      approach to screen protein targets with malleable binding
                      sites.},
      cin          = {IAS-5 / INM-9},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121},
      pnm          = {5241 - Molecular Information Processing in Cellular Systems
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5241},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:34136757},
      UT           = {WOS:000662229400006},
      doi          = {10.1021/acsptsci.0c00215},
      url          = {https://juser.fz-juelich.de/record/891037},
}