Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3ß Inhibitors
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2021Author(s)
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10.1021/acs.jmedchem.0c02146Metadata
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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. (2021). Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3ß Inhibitors. Journal of medicinal chemistry, 65 (2) , 1283–1301. 10.1021/acs.jmedchem.0c02146.Rights
Abstract
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.
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http://dx.doi.org/10.1021/acs.jmedchem.0c02146Publisher
American Chemical Society (ACS)Collections
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