title: Molecular view of ligands specificity for CAG repeats in anti-Huntington therapy.
abstract: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Bochicchio
authors.affiliation: Department of Oncology, Hematology and Stem Cell Transplantation, RWTH Aachen University , D-52074 Aachen, North Rhine-Westphalia, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Rossetti
authors.affiliation: Department of Pharmaceutical Sciences, Università di Perugia , Via del Liceo 1, I-06123 Perugia, Perugia, Italy.
authors.forename: Oriana
authors.initials: O
authors.lastname: Tabarrini
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Sigmund-Freud-Strasse 25, D-53127 Bonn, North Rhine-Westphalia, Germany.
authors.forename: Sybille
authors.initials: S
authors.lastname: Krauβ
authors.forename: Paolo
authors.initials: P
authors.lastname: Carloni
mesh_terms: D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics*; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D012333:RNA, Messenger / Q000737:chemistry* / Q000235:genetics*; D013816:Thermodynamics; D018911:Trinucleotide Repeats / Q000235:genetics*
chemical_list: D007093:Imidazoles; D008024:Ligands; D012333:RNA, Messenger