Journal Article

FZJ-2016-00239

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular View of Ligands Specificity for CAG Repeats in Anti-Huntington Therapy

Bochicchio, A. ; Rossetti, G. (Corresponding author)FZJ* ; Tabarrini, O. ; Krauβ, S. ; Carloni, P.FZJ*

2015
American Chemical Society (ACS) Washington, DC

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Please use a persistent id in citations: doi:10.1021/acs.jctc.5b00208

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.

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Contributing Institute(s):

1. Jülich Supercomputing Center (JSC)
2. Computational Biomedicine (IAS-5)
3. Computational Biomedicine (INM-9)
4. GRS (GRS Jülich ; German Research School for Simulation Sciences)

Research Program(s):

1. 511 - Computational Science and Mathematical Methods (POF3-511) (POF3-511)
2. 572 - (Dys-)function and Plasticity (POF3-572) (POF3-572)

Appears in the scientific report 2015

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Database coverage:
; Current Contents - Physical, Chemical and Earth Sciences ; IF >= 5 ; JCR ; No Authors Fulltext ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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