Molecular view of ligands specificity for CAG repeats in anti-Huntington therapy
| Autor: | Oriana Tabarrini, Anna Bochicchio, Giulia Rossetti, Paolo Carloni, Sybille Krauβ |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
chemistry [Imidazoles]
pharmacology [Imidazoles] Biology Molecular Dynamics Simulation Ligands genetics [Huntington Disease] genetics [RNA Messenger] Trinucleotide Repeats Huntingtin Protein medicine Humans ddc:610 RNA Messenger Physical and Theoretical Chemistry Genetics Messenger RNA Molecular Structure Ligand Rational design Metadynamics Genetic disorder Imidazoles RNA medicine.disease Affinities Computer Science Applications drug therapy [Huntington Disease] Huntington Disease Biochemistry chemistry [RNA Messenger] genetics [Trinucleotide Repeats] Thermodynamics |
| Zdroj: | Journal of chemical theory and computation 11(10), 4911-4922 (2015). doi:10.1021/acs.jctc.5b00208 |
| ISSN: | 1549-9626 |
| DOI: | 10.1021/acs.jctc.5b00208 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|