dc.contributor.author | Andreev, Stanislav | |
dc.contributor.author | Pantsar, Tatu | |
dc.contributor.author | Tesch, Roberta | |
dc.contributor.author | Kahlke, Niclas | |
dc.contributor.author | El-Gokha, Ahmed | |
dc.contributor.author | Ansideri, Francesco | |
dc.contributor.author | Grätz, Lukas | |
dc.contributor.author | Romasco, Jenny | |
dc.contributor.author | Sita, Giulia | |
dc.contributor.author | Geibel, Christian | |
dc.contributor.author | Lämmerhofer, Michael | |
dc.contributor.author | Tarozzi, Andrea | |
dc.contributor.author | Knapp, Stefan | |
dc.contributor.author | Laufer, Stefan A. | |
dc.contributor.author | Koch, Pierre | |
dc.date.accessioned | 2021-09-02T10:13:37Z | |
dc.date.available | 2021-09-02T10:13:37Z | |
dc.date.issued | 2021 | |
dc.identifier.uri | https://erepo.uef.fi/handle/123456789/26031 | |
dc.description.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. | |
dc.language.iso | eng | |
dc.publisher | American Chemical Society (ACS) | |
dc.relation.ispartofseries | Journal of medicinal chemistry | |
dc.relation.uri | http://dx.doi.org/10.1021/acs.jmedchem.0c02146 | |
dc.rights | In copyright 1.0 | |
dc.subject | Glycogen Synthase Kinase 3 beta | |
dc.subject | 9H-pyrimido[4,5-b]indole | |
dc.subject | WaterMap | |
dc.subject | Molecular Dynamics Simulation | |
dc.title | Addressing a Trapped High-Energy Water: Design and Synthesis of Highly Potent Pyrimidoindole-Based Glycogen Synthase Kinase-3ß Inhibitors | |
dc.description.version | final draft | |
dc.contributor.department | School of Pharmacy, Activities | |
uef.solecris.id | 80288604 | en |
dc.type.publication | Tieteelliset aikakauslehtiartikkelit | |
dc.relation.doi | 10.1021/acs.jmedchem.0c02146 | |
dc.description.reviewstatus | peerReviewed | |
dc.format.pagerange | 1283–1301 | |
dc.relation.issn | 0022-2623 | |
dc.relation.issue | 2 | |
dc.relation.volume | 65 | |
dc.rights.accesslevel | openAccess | |
dc.type.okm | A1 | |
uef.solecris.openaccess | Ei | |
dc.rights.copyright | © 2021 American Chemical Society | |
dc.type.displayType | Artikkeli | fi |
dc.type.displayType | Article | en |
uef.rt.id | 14719 | en |
dc.rights.url | https://rightsstatements.org/page/InC/1.0/ | |