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

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• 作者：Anna Bochicchio ; Giulia Rossetti ; Oriana Tabarrini ; Sybille Krau尾 ; Paolo Carloni
• 刊名：Journal of Chemical Theory and Computation
• 出版年：2015
• 出版时间：October 13, 2015
• 年：2015
• 卷：11
• 期：10
• 页码：4911-4922
• 全文大小：610K
• ISSN：1549-9626

文摘

Huntington鈥檚 disease is a fatal and devastating neurodegenerative genetic disorder for which there is currently no cure. It is characterized by Huntingtin protein鈥檚 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 K_d = 60(30) nM. The second consists of a 4-phenyl dihydroimidazole and 4鈥?H-indole dihydroimidazole connected by a C鈥揅 bond (K_d = 700(80) nM). Our calculations reproduce the experimental affinities and uncover the recognition pattern between ligands鈥?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.