“First Principle” Concept in Designing Small Molecules for Targeting RNA Expansion Repeats

Title: Unleashing the Power of «First Principle» in Designing Small Molecules for Targeting RNA Expansion Repeats


In recent years, the discovery of RNA expansion repeats as causative factors in various neurodegenerative disorders has sparked intense interest in developing small molecules that can target and modulate these repeat sequences. The «First Principle» concept in molecular design has emerged as a powerful approach to creating highly selective and efficient small molecules for this purpose. In this blog, we will explore the significance of the «First Principle» concept in designing small molecules for targeting RNA expansion repeats, focusing on key points such as the role of RNA expansion repeats in neurodegenerative disorders, the challenge of selective targeting, and the promise of the «First Principle» approach.

Key Points:

  1. Understanding RNA Expansion Repeats in Neurodegenerative Disorders:
    • RNA expansion repeats are stretches of repetitive nucleotide sequences found within certain genes, implicated in several devastating neurodegenerative disorders.
    • These repeats can result in abnormal protein production, RNA toxicity, and various cellular dysfunctions leading to disease progression.
  2. The Challenge of Selective Targeting:
    • Designing small molecules that selectively target RNA expansion repeats is a significant challenge due to the complex structure and dynamic nature of RNA.
    • Achieving specificity is critical to minimize off-target effects and maximize therapeutic efficacy.
  3. The Promise of the «First Principle» Approach:
    • The «First Principle» approach in molecular design involves understanding the fundamental properties of RNA expansion repeats and developing small molecules based on those principles.
    • By considering the repeat structure, secondary structures, and binding motifs, small molecules can be designed to specifically bind and modulate the RNA repeat sequences.
  4. Rational Design and Optimization:
    • «First Principle» design incorporates computational modeling, molecular dynamics simulations, and structure-based drug design to optimize small molecules for specific interactions with the RNA repeat sequences.
    • Iterative design cycles allow for the refinement and improvement of small molecules for enhanced target selectivity and binding affinity.
  5. Other Considerations and Challenges:
    • Cellular permeability, stability, and toxicity are important factors to consider in the development of small molecules targeting RNA expansion repeats.
    • In vitro and in vivo validation studies are necessary to assess the efficacy and safety of these small molecules.
  6. Future Prospects and Collaborations:
    • The «First Principle» approach provides a foundation for the discovery and development of small molecules that can selectively target RNA expansion repeats.
    • Collaborations between RNA biologists, chemists, and computational scientists are crucial for advancing this field and translating promising molecules into therapeutic interventions.


The «First Principle» concept offers tremendous potential in the design of small molecules specifically tailored to target RNA expansion repeats associated with neurodegenerative disorders. By understanding the fundamental principles governing the structure and behavior of these repetitive RNA sequences, researchers can develop small molecules that selectively modulate their function. The «First Principle» approach, coupled with computational modeling and drug design techniques, holds promise in advancing the field of RNA-targeted therapeutics for neurodegenerative disorders. Continued research and collaborations will pave the way for breakthrough discoveries and the development of innovative treatments that address the underlying causes of these debilitating diseases.