In silico Vorhersage von Kleinmolekül-Liganden für Klasse Frizzled GPCRs und Untersuchung der strukturellen Basis von FZD Signalwegen
Bioinformatik und Theoretische Biologie
Pharmazie
Zusammenfassung der Projektergebnisse
The project was investigating the class F G protein-coupled receptors (GPCRs) Frizzleds (FZDs) which are not only relevant for embryonal and cell development, but also promising drug targets in diverse cancers. However, large knowledge gaps regarding FZD-mediated signalling mechanisms, their signalling specificity and the modulation of this signalling by the endogenous ligands WNTs still exist. FZD-targeting small molecule modulators can serve as helpful tools to unravel FZD-mediated signalling further and set a basis for future potential drug candidates. So far, only few FZD- targeting small molecule modulators are known, hence, one of the goals of this project was to discover novel small molecule ligands that bind to FZDs. In this project a series of novel ligands binding to and potentially modulating FZD7 was identified using in silico docking screens of large molecular libraries. The insights gained from this study can be used as a basis for future strategies to target FZDs in in silico docking screens, for example using the improved knowledge of the potential small molecule binding site and small molecule interactions. This will help the search for improved small molecule modulators and future drug candidates. Another goal was to study the complex conformation and orientation of FZD and its downstream effectors. A molecular understanding of this complex and the interactions between FZD and its main transducer Dishevelled (DVL) is important to better understand the FZD- mediated signalling pathways and how to modulate them. In this project, progress has been made to understand this complex in more detail and to elucidate interactions. If we can understand the FZD-DVL complex in more detail, it might lead to a better understanding of how signalling is transduced by DVL, why there are different signalling pathways that can be induced by DVL depending on the involved FZD-paralog and how G proteins or other transducer molecules fit into this. An improved understanding of these mechanisms will also improve the knowledge of how these signalling pathways can be targeted in the treatment of diseases such as cancers. With this study, which is currently still ongoing, we are one step closer to understand these processes better. Other research projects investigating activation mechanisms of FZD-mediated signalling arose during the funding period, including a study investigating intra-molecular activation mechanisms. This study was published in Nature Communications and aids further towards an improved understanding of FZD-mediated signalling. In summary, valuable progress towards an improved understanding of FZD-mediated signalling was made. This includes progress towards the development and discovery of novel FZD-targeting small molecule modulators, molecular activation mechanisms of the receptor and interactions and complex conformation of FZDs with their downstream effectors. All gained knowledge will benefit the exploitation of FZDs as drug targets in diverse diseases, especially cancers.
Projektbezogene Publikationen (Auswahl)
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Pathway selectivity in Frizzleds is achieved by conserved micro-switches defining pathway-determining, active conformations. Nature Communications, 14(1).
Grätz, Lukas; Kowalski-Jahn, Maria; Scharf, Magdalena M.; Kozielewicz, Pawel; Jahn, Michael; Bous, Julien; Lambert, Nevin A.; Gloriam, David E. & Schulte, Gunnar
