This title appears in the Scientific Report : 2015 

Molecular View of Ligands Specificity for CAG Repeats in Anti-Huntington Therapy
Bochicchio, Anna
Rossetti, Giulia (Corresponding author) / Tabarrini, Oriana / Krauβ, Sybille / Carloni, Paolo
GRS; GRS Jülich; German Research School for Simulation Sciences
Computational Biomedicine; INM-9
Computational Biomedicine; IAS-5
Jülich Supercomputing Center; JSC
Journal of chemical theory and computation, 11 (2015) 10, S. 4911 - 4922
Washington, DC American Chemical Society (ACS) 2015
10.1021/acs.jctc.5b00208
26574279
Journal Article
(Dys-)function and Plasticity
Computational Science and Mathematical Methods
Please use the identifier: http://dx.doi.org/10.1021/acs.jctc.5b00208 in citations.
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.