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This title appears in the Scientific Report : 2015 

Molecular View of Ligands Specificity for CAG Repeats in Anti-Huntington Therapy

Molecular View of Ligands Specificity for CAG Repeats in Anti-Huntington Therapy

Huntington’s disease is a fatal and devastating neurodegenerative genetic disorder for which there is currently no cure. It is characterized by Huntingtin protein’s mRNA transcripts with 36 or more CAG repeats. Inhibiting the formation of pathological complexes between these expanded transcripts and...

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Personal Name(s): Bochicchio, Anna
Rossetti, Giulia (Corresponding author) / Tabarrini, Oriana / Krauβ, Sybille / Carloni, Paolo
Contributing Institute: GRS; GRS
Computational Biomedicine; INM-9
Computational Biomedicine; IAS-5
Jülich Supercomputing Center; JSC
Published in: Journal of chemical theory and computation, 11 (2015) 10, S. 4911 - 4922
Imprint: Washington, DC American Chemical Society (ACS) 2015
DOI: 10.1021/acs.jctc.5b00208
PubMed ID: 26574279
Document Type: Journal Article
Research Program: (Dys-)function and Plasticity
Computational Science and Mathematical Methods
Publikationsportal JuSER
Please use the identifier: http://dx.doi.org/10.1021/acs.jctc.5b00208 in citations.

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Huntington’s disease is a fatal and devastating neurodegenerative genetic disorder for which there is currently no cure. It is characterized by Huntingtin protein’s mRNA transcripts with 36 or more CAG repeats. Inhibiting the formation of pathological complexes between these expanded transcripts and target proteins may be a valuable strategy against the disease. Yet, the rational design of molecules specifically targeting the expanded CAG repeats is limited by the lack of structural information. Here, we use well-tempered metadynamics-based free energy calculations to investigate pose and affinity of two ligands targeting CAG repeats for which affinities have been previously measured. The first consists of two 4-guanidinophenyl rings linked by an ester group. It is the most potent ligand identified so far, with Kd = 60(30) nM. The second consists of a 4-phenyl dihydroimidazole and 4–1H-indole dihydroimidazole connected by a C–C bond (Kd = 700(80) nM). Our calculations reproduce the experimental affinities and uncover the recognition pattern between ligands’ and their RNA target. They also provide a molecular basis for the markedly different affinity of the two ligands for CAG repeats as observed experimentally. These findings may pave the way for a structure-based hit-to-lead optimization to further improve ligand selectivity toward CAG repeat-containing mRNAs.

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