Andreev, Stanislav and Pantsar, Tatu and Tesch, Roberta and Kahlke, Niclas and El-Gokha, Ahmed and Ansideri, Francesco and Grätz, Lukas and Romasco, Jenny and Sita, Giulia and Geibel, Christian and Laemmerhofer, Michael and Tarozzi, Andrea and Knapp, Stefan and Laufer, Stefan A. and Koch, Pierre (2022) Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3 beta Inhibitors. JOURNAL OF MEDICINAL CHEMISTRY, 65 (2). pp. 1283-1301. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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-3 beta (GSK-3 beta) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ORGANIC-MOLECULES; PROTEIN; KINASE; THERMODYNAMICS; RECOGNITION; SELECTIVITY; PREDICTION; DISCOVERY; SOLVENT; CELL |
| Subjects: | 500 Science > 540 Chemistry & allied sciences 600 Technology > 610 Medical sciences Medicine 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 16 Feb 2024 10:53 |
| Last Modified: | 16 Feb 2024 10:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/58120 |
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