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Identification of Novel Histamine H4 Ligands by Virtual Screening on Molecular Dynamics Ensembles

Authors

  • Róbert Kiss,

    1. mcule.com Ltd. Vendel utca 15–17, B/2/6, H-1096 Budapest, Hungary
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  • Balázs Jójárt,

    1. Department of Chemical Informatics, Faculty of Education, University of Szeged, Boldogasszony sgt. 6., H-6725, Szeged, Hungary
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  • Éva Schmidt,

    1. Gedeon Richter Plc, Gyömrői út 19–21., H-1103, Budapest, Hungary
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  • Béla Kiss,

    1. Gedeon Richter Plc, Gyömrői út 19–21., H-1103, Budapest, Hungary
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  • György M. Keserű

    Corresponding author
    1. Gedeon Richter Plc, Gyömrői út 19–21., H-1103, Budapest, Hungary
    2. Department of General and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért tér 4., H-1111, Budapest, Hungary
    3. Present address: Research Centre for Natural Sciences, Hungarian Academy of Sciences, Pusztaszeri út 59–67., H-1025 Budapest, Hungary
    • Gedeon Richter Plc, Gyömrői út 19–21., H-1103, Budapest, Hungary

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Abstract

We report the identification of novel histamine H4 receptor ligands by ensemble docking on homology model conformers derived from molecular dynamics simulations. Selected receptor models from the trajectories demonstrated superior virtual screening performance compared to the initial models. The ensemble of the best models was able to retrieve a diverse set of known H4 ligands. Prospective virtual screening against these models and subsequent in vitro experimental validation identified novel H4 ligands. Compound 3 showing highest affinity and ligand efficiency represents an interesting scaffold for further medicinal chemistry exploration.

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