The massive of the genome sequencing data has established a clear connection between several neurol. and neuromuscular disorders, and expansions of short nucleotide repeats. To name few, these maladies include Myotonic Muscular Dystrophy, Machado-Joseph disease, Huntington disease, Lou Gehrig's disease. In numerous instances it was demonstrated that the small organic mols. therapeutic strategy - a well-proven tool of modern medicine - also can be utilized for treatment these, otherwise non-curable, disorders by targeting specific RNA sequences of the overexpressed expansions repeats. The ligand-target mechanism when the RNA expansion repeats are targeted with small mols. has been shown working in multiple research studies including animal models. However, one of the limiting obstacles for finding new high-quality lead mols. is that most of the com. high throughput screening (HTS) libraries are biased towards the protein affinity chem. space. The unique distinction of the RNA affinity chem. space requires different weight factors that contribute to physicochem. interactions of a ligand-target ensemble in the RNA chem. space vs in the protein one. One of the most advantageous approaches is to target RNA's with designer macrocyclic compounds The use of macrocycles for therapeutic RNA targeting is especially alluring as selective G-Quadruplex RNA (as well as DNA) ligands. As a back-end selectivity reinforcement approach, we propose the 3D shape and electrostatic field similarity virtual screening method using the complimentary trinucleotide sequences as reference training sets.