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Download fileAddressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3β Inhibitors
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posted on 2021-07-02, 14:09 authored by Stanislav Andreev, Tatu Pantsar, Roberta Tesch, Niclas Kahlke, Ahmed El-Gokha, Francesco Ansideri, Lukas Grätz, Jenny Romasco, Giulia Sita, Christian Geibel, Michael Lämmerhofer, Andrea Tarozzi, Stefan Knapp, Stefan A. Laufer, Pierre KochIn 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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hydration sitelocationkinome selectivity profileHigh-Energy WaterSH-SY 5Y cellsligand bindingWaterMap analysisGSK -3 autophosphorylationmolecule bindinginhibitorwater moleculemicrosecond timescaleco-crystallized glycogen synthase k...binding sitePotent Pyrimidoindole-Based Glycoge...IC 50 value6 nMdynamics simulationstarget engagement