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@ARTICLE{Loschwitz:904335,
      author       = {Loschwitz, Jennifer and Jäckering, Anna and Keutmann,
                      Monika and Eberle, Raphael J. and Olagunju, Maryam and
                      Coronado, Monika Aparecida and Olubiyi, Olujide and Strodel,
                      Birgit},
      title        = {{N}ovel inhibitors of the main protease enzyme of
                      {SARS}-{C}o{V}-2 identified via molecular dynamics
                      simulation-guided in vitro assay},
      journal      = {Bioorganic chemistry},
      volume       = {111},
      issn         = {0045-2068},
      address      = {San Diego, Calif.},
      publisher    = {Elsevier},
      reportid     = {FZJ-2021-05905},
      pages        = {104862 -},
      year         = {2021},
      abstract     = {For the COVID-19 pandemic caused by SARS-CoV-2, there are
                      currently no effective drugs or vaccines to treat this
                      coronavirus infection. In this study, we focus on the main
                      protease enzyme of SARS-CoV-2, 3CLpro, which is critical for
                      viral replication. We employ explicit solvent molecular
                      dynamics simulations of about 150 compounds docked into
                      3CLpro’s binding site and that had emerged as good main
                      protease ligands from our previous in silico screening of
                      over 1.2 million compounds. By incoporating protein dynamics
                      and applying a range of structural descriptors, such as the
                      ability to form specific contacts with the catalytic dyad
                      residues of 3CLpro and the structural fluctuations of the
                      ligands in the binding site, we are able to further refine
                      our compound selection. Fourteen compounds including
                      estradiol shown to be the most promising based on our
                      calculations were procured and screened against recombinant
                      3CLpro in a fluorescence assay. Eight of these compounds
                      have significant activity in inhibiting the SARS-CoV-2 main
                      protease. Among these are corilagin, a gallotannin, and
                      lurasidone, an antipsychotic drug, which emerged as the most
                      promising natural product and drug, respectively, and might
                      thus be candidates for drug repurposing for the treatment of
                      COVID-19. In addition, we also tested the inhibitory
                      activity of testosterone, and our results reveal
                      testosterone as possessing moderate inhibitory potency
                      against the 3CLpro enzyme, which may thus provide an
                      explanation why older men are more severely affected by
                      COVID-19.},
      cin          = {IBI-7},
      ddc          = {540},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {33862474},
      UT           = {WOS:000656967800004},
      doi          = {10.1016/j.bioorg.2021.104862},
      url          = {https://juser.fz-juelich.de/record/904335},
}