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

Tatu Pantsar, Philipp D. Kaiser, Mark Kudolo, Michael Forster, Ulrich Rothbauer and Stefan A. Laufer ()
Additional contact information
Tatu Pantsar: Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen
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
Stefan A. Laufer: Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-022-28164-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28164-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-022-28164-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().