Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3β Inhibitors

In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC50 value of our co-crystallized glycogen synthase kinase-3β (GSK-3β) inh...

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Published in:Journal of medicinal chemistry 2022-01, Vol.65 (2), p.1283-1301
Main Authors: Andreev, Stanislav, Pantsar, Tatu, Tesch, Roberta, Kahlke, Niclas, El-Gokha, Ahmed, Ansideri, Francesco, Grätz, Lukas, Romasco, Jenny, Sita, Giulia, Geibel, Christian, Lämmerhofer, Michael, Tarozzi, Andrea, Knapp, Stefan, Laufer, Stefan A, Koch, Pierre
Format: Article
Language:English
Subjects:
Cell Proliferation
Drug Design
Glycogen Synthase Kinase 3 beta - antagonists & inhibitors
Humans
Molecular Dynamics Simulation
Neuroblastoma - drug therapy
Neuroblastoma - enzymology
Neuroblastoma - pathology
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacology
Pyrimidines - chemistry
Structure-Activity Relationship
Tumor Cells, Cultured
Water - chemistry
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Summary:In small molecule binding, water is not a passive bystander but rather takes an active role in the binding site, which may be decisive for the potency of the inhibitor. Here, by addressing a high-energy water, we improved the IC50 value of our co-crystallized glycogen synthase kinase-3β (GSK-3β) inhibitor by nearly two orders of magnitude. Surprisingly, our results demonstrate that this high-energy water was not displaced by our potent inhibitor (S)-3-(3-((7-ethynyl-9H-pyrimido­[4,5-b]­indol-4-yl)­(methyl)­amino)­piperidin-1-yl)­propanenitrile ((S)-15, IC50 value of 6 nM). Instead, only a subtle shift in the location of this water molecule resulted in a dramatic decrease in the energy of this high-energy hydration site, as shown by the WaterMap analysis combined with microsecond timescale molecular dynamics simulations. (S)-15 demonstrated both a favorable kinome selectivity profile and target engagement in a cellular environment and reduced GSK-3 autophosphorylation in neuronal SH-SY5Y cells. Overall, our findings highlight that even a slight adjustment in the location of a high-energy water can be decisive for ligand binding.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.0c02146