Design of spᶟ — Enriched α-Helix-Mimetics Library

Title: Exploring New Horizons in Drug Design: The Design of sp³-Enriched α-Helix-Mimetics Library


In the realm of drug discovery, the design of novel small molecules with the ability to mimic the structural and functional properties of α-helices has garnered significant interest. α-helices play crucial roles in protein-protein interactions (PPIs) and are involved in numerous biological processes. Recently, the concept of designing sp³-enriched α-helix-mimetics libraries has emerged as a promising strategy to explore uncharted chemical space and create potential therapeutics. In this blog post, we will delve into the key points surrounding the design of sp³-enriched α-helix-mimetics libraries and their potential applications in drug discovery.

Key Points

  1. Importance of α-Helices and Protein-Protein Interactions: α-helices are fundamental structural elements found in proteins and are essential in mediating protein-protein interactions. PPIs govern various biological processes, and dysregulation of these interactions can lead to diseases such as cancer, neurodegenerative disorders, and infectious diseases. Targeting PPIs through α-helix-mimetics presents an attractive approach for the development of therapeutics.
  2. The Challenge of Designing α-Helix-Mimetics: Designing molecules that mimic the structure and functionality of α-helices presents significant challenges due to their complex three-dimensional (3D) structure and the importance of stabilizing intramolecular interactions. Traditional small molecule design approaches may not adequately address these challenges, leading to limited success in targeting α-helices. Therefore, novel strategies, such as the design of sp³-enriched α-helix-mimetics libraries, are gaining attention.
  3. sp³-Enriched α-Helix-Mimetics Library Design: The design of sp³-enriched α-helix-mimetics libraries involves the incorporation of sp³-rich building blocks within the molecule’s backbone. The inclusion of sp³ hybridized carbon centers allows for increased molecular complexity, improved conformational space, and enhanced mimicry of α-helices. Rational design principles guide the selection and assembly of building blocks to generate diverse libraries that can target specific protein targets or protein-protein interactions.
  4. Structural Features and Drug-like Properties: sp³-enriched α-helix-mimetics libraries showcase unique structural features, including rigidity and helical shape, which are critical for effective mimicry of α-helices. These libraries can be designed to possess drug-like properties such as good solubility, stability, and cell permeability. The rational incorporation of diverse functional groups further enhances their potential for selective target engagement.
  5. Synthesis and Screening Strategies: The synthesis of sp³-enriched α-helix-mimetics libraries can be achieved through diverse synthetic methodologies, including solid-phase synthesis and solution-phase synthesis. High-throughput screening and structure-based design techniques play a vital role in identifying hit compounds with the desired biological activity. Iterative optimization and medchem approaches further refine the library to enhance potency, selectivity, and drug-like properties.
  6. Applications and Therapeutic Potential: sp³-enriched α-helix-mimetics libraries have the potential to revolutionize drug discovery by targeting previously challenging protein-protein interactions. These libraries can be explored for various therapeutic areas, including cancer, infectious diseases, and neurodegenerative disorders. By selectively targeting specific α-helices involved in disease-related PPIs, sp³-enriched α-helix-mimetics offer new avenues for therapeutic intervention and the potential to address previously undruggable targets.


The design of sp³-enriched α-helix-mimetics libraries represents a promising frontier in drug discovery, offering unprecedented opportunities to target protein-protein interactions and develop therapeutics for challenging diseases. By incorporating sp³-rich building blocks and leveraging rational design principles, these libraries enable the exploration of uncharted chemical space and the development of small molecules that mimic the structural and functional aspects of α-helices. As research into sp³-enriched α-helix-mimetics progresses, we anticipate exciting advancements in drug development and the emergence of novel therapeutics with the potential to reshape the treatment landscape for a variety of diseases.