The prerequisite of this structure-based lead-compound design (SBLD) approach is the understanding of the various conformations adopted by an RNA target. Interestingly, many disease-causing RNA molecules, especially those triggering neuromuscular diseases, include repetitive sequences of nucleotides that have been shown to adopt hairpin structures . These repeat expansions include trinucleotide repeats, which cause myotonic dystrophy (DM), Huntington disease (HD), fragile X syndrome (FXS), and others . For these diseases, RNA internal loop motifs contained within the folded state has been shown to yield RNA gain-of-function. For example, expansion of CAG repeats found in Huntingtin gene translates into toxic polyglutamine (polyQ) proteins and sequesters proteins such as MBNL1 that cause HD. These internal loops, which vary in composition and size, sequester RNA-binding proteins involved in post-transcriptional gene regulation in foci either in nucleus or cytoplasm . Targeting these loops with small molecules can rescue various disease-associated phenotypes. Structural and modeling studies suggest that small molecules, which selectively target the loop regions in repeat expansions, can exploit these binding pockets . RNA internal loops have varying levels of conformational flexibility depending on the nucleotide composition and the neighboring base pairs. Residues in RNA internal loops can stack or unstack (stack ↔ unstack) from helical axis or rotate around the glycosidic bond (anti ↔ syn) that can stabilize the duplexes . Among all nucleotides, guanosine have the highest tendency to adopt the syn conformation . As a result, understanding the different conformations adopted by unique RNA loop motifs can help structure-based drug design.