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Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors

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  • Tatu Pantsar

    (Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen
    University of Eastern Finland)

  • Philipp D. Kaiser

    (NMI Natural and Medical Sciences Institute at the University of Tuebingen)

  • Mark Kudolo

    (Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen)

  • Michael Forster

    (Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen)

  • Ulrich Rothbauer

    (NMI Natural and Medical Sciences Institute at the University of Tuebingen
    Eberhard Karls University Tuebingen
    University of Tuebingen)

  • Stefan A. Laufer

    (Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen
    University of Tuebingen
    Tuebingen Center for Academic Drug Discovery & Development (TüCAD2))

Abstract

Target residence time plays a crucial role in the pharmacological activity of small molecule inhibitors. Little is known, however, about the underlying causes of inhibitor residence time at the molecular level, which complicates drug optimization processes. Here, we employ all-atom molecular dynamics simulations (~400 μs in total) to gain insight into the binding modes of two structurally similar p38α MAPK inhibitors (type I and type I½) with short and long residence times that otherwise show nearly identical inhibitory activities in the low nanomolar IC50 range. Our results highlight the importance of protein conformational stability and solvent exposure, buried surface area of the ligand and binding site resolvation energy for residence time. These findings are further confirmed by simulations with a structurally diverse short residence time inhibitor SB203580. In summary, our data provide guidance in compound design when aiming for inhibitors with improved target residence time.

Suggested Citation

  • Tatu Pantsar & Philipp D. Kaiser & Mark Kudolo & Michael Forster & Ulrich Rothbauer & Stefan A. Laufer, 2022. "Decisive role of water and protein dynamics in residence time of p38α MAP kinase inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28164-4
    DOI: 10.1038/s41467-022-28164-4
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    Cited by:

    1. B. L. Dargaville & D. W. Hutmacher, 2022. "Water as the often neglected medium at the interface between materials and biology," Nature Communications, Nature, vol. 13(1), pages 1-10, December.

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