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What doesn't fit is made to fit: Pim-1 kinase adapts to the configuration of stilbene-based inhibitors.
- Source :
-
Archiv der Pharmazie [Arch Pharm (Weinheim)] 2024 Jun; Vol. 357 (6), pp. e2400094. Date of Electronic Publication: 2024 Apr 17. - Publication Year :
- 2024
-
Abstract
- Recently, we have developed novel Pim-1 kinase inhibitors starting from a dihydrobenzofuran core structure using a computational approach. Here, we report the design and synthesis of stilbene-based Pim-1 kinase inhibitors obtained by formal elimination of the dihydrofuran ring. These inhibitors of the first design cycle, which were obtained as inseparable cis/trans mixtures, showed affinities in the low single-digit micromolar range. To be able to further optimize these compounds in a structure-based fashion, we determined the X-ray structures of the protein-ligand-complexes. Surprisingly, only the cis-isomer binds upon crystallization of the cis/trans-mixture of the ligands with Pim-1 kinase and the substrate PIMTIDE, the binding mode being largely consistent with that predicted by docking. After crystallization of the exclusively trans-configured derivatives, a markedly different binding mode for the inhibitor and a concomitant rearrangement of the glycine-rich loop is observed, resulting in the ligand being deeply buried in the binding pocket.<br /> (© 2024 The Authors. Archiv der Pharmazie published by Wiley‐VCH GmbH on behalf of Deutsche Pharmazeutische Gesellschaft.)
- Subjects :
- Humans
Binding Sites
Crystallography, X-Ray
Drug Design
Ligands
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors chemistry
Protein Kinase Inhibitors chemical synthesis
Proto-Oncogene Proteins c-pim-1 antagonists & inhibitors
Proto-Oncogene Proteins c-pim-1 metabolism
Stilbenes chemistry
Stilbenes pharmacology
Stilbenes chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 1521-4184
- Volume :
- 357
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Archiv der Pharmazie
- Publication Type :
- Academic Journal
- Accession number :
- 38631036
- Full Text :
- https://doi.org/10.1002/ardp.202400094