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Recently, it has been shown that such G<jats:sub>4<\/jats:sub>C<jats:sub>2<\/jats:sub> repetitions can fold into G\u2010quadruplex (G4) secondary structures. These G4s have been selectively stabilized by small\u2010molecule binders, furnishing proof\u2010of\u2010principle that targeting these non\u2010canonical nucleic acid sequences represents a novel and effective therapeutic strategy to tackle neurodegenerative disorders. However, precise information on the mechanism of action of these compounds is still lacking. Here, by performing <jats:italic>in silico<\/jats:italic> investigations, we unraveled the molecular basis for the selectivity of a series of known structurally related <jats:italic>C9orf72<\/jats:italic> G4\u2010binders. Moreover, we investigated the binding properties of a strong and selective metal\u2010based G4 stabilizer, the Au<jats:sup>I<\/jats:sup> bis\u2010N\u2010heterocyclic carbene (NHC) complex \u2013 Au(TMX)<jats:sub>2<\/jats:sub> \u2013 showing that it moderately stabilizes G<jats:sub>4<\/jats:sub>C<jats:sub>2<\/jats:sub> G4 RNA by F\u00f6rster resonance energy transfer (FRET) DNA melting assays. Using metadynamics (metaD) simulations, the Au(TMX)<jats:sub>2<\/jats:sub> binding mode and the associated free\u2010energy landscape were also evaluated. This information paves the way for developing improved compounds to tackle ALS\/FTD neurodegenerative disorders.<\/jats:p>","DOI":"10.1002\/cbic.202400974","type":"journal-article","created":{"date-parts":[[2024,12,13]],"date-time":"2024-12-13T05:30:32Z","timestamp":1734067832000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unraveling the Molecular Basis for G\u2010Quadruplex\u2010Binders to ALS\/FTD\u2010Associated G4C2 Repeats of the <i>C9orf72<\/i> Gene"],"prefix":"10.1002","volume":"26","author":[{"given":"Luisa","family":"D'Anna","sequence":"first","affiliation":[{"name":"Department of Biological, Chemical, and Pharmaceutical Sciences Technologies, Universit\u00e0 di Palermo  Viale delle Scienze Edificio 17 90128 Palermo Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darren","family":"Wragg","sequence":"additional","affiliation":[{"name":"Chair of Medicinal and Bioinorganic Chemistry School of Natural Sciences Department of Chemistry Technical University of Munich (TUM)  Lichtenbergstr. 4 85748 Garching b. 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