The massive of the genome sequencing data has established a clear connection between several neurological 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 molecules 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 molecules has been shown working in multiple research studies including animal models. However, one of the limiting obstacles for finding new high-quality lead molecules is that most of the commercial high throughput screening (HTS) libraries are biased towards the protein affinity chemical space. The unique distinction of the RNA affinity chemical space requires different weight factors that contribute to physicochemical interactions of a ligand-target ensemble in the RNA chemical 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.

“First principle” concept in designing small molecules for targeting RNA expansion repeats

2019 Fall National Meeting

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