Macrocyclic Peptidomimetics: Library Design And Synthesis

Title: Macrocyclic Peptidomimetics: Design and Synthesis of an Expanding Library


Macrocyclic peptidomimetics, a class of synthetic compounds that mimic the structures and properties of peptides, have gained significant attention in drug discovery. Their unique three-dimensional structures and diverse chemical scaffolds make them attractive candidates for targeting protein-protein interactions, receptor signaling, and enzyme activity. In this blog, we will focus on the key points of library design and synthesis of macrocyclic peptidomimetics, highlighting their potential as a valuable resource for drug development.

Key Points:

  1. Library Design: Harnessing Diversity for Target Exploration:
    • The design of a macrocyclic peptidomimetic library involves the strategic selection of diverse chemical building blocks and structural motifs.
    • Libraries may be designed to target specific therapeutic areas, taking into consideration the desired biological activity and target affinity.
    • The size and complexity of the library depend on the intended screening strategy and the available synthetic capabilities.
  2. Structural Diversity: Exploring Different Macrocyclic Scaffolds:
    • Macrocyclic peptidomimetics offer a wide range of structural diversity due to the varying combinations of backbone modifications, side chain substitutions, and ring sizes.
    • Macrocycles can adopt different conformations and exhibit unique binding properties, enabling them to target challenging protein surfaces and regions.
  3. Synthetic Approaches: Overcoming Challenges in Macrocycle Synthesis:
    • The synthesis of macrocyclic peptidomimetics can pose challenges due to the formation of intramolecular bonds and increased flexibility.
    • Modern synthetic techniques, including solid-phase synthesis, solution-phase synthesis, and fragment coupling, have been employed to overcome these challenges.
    • Advances in synthetic methods have enabled the efficient assembly of complex macrocyclic peptidomimetics, facilitating library synthesis and discovery efforts.
  4. Screening Strategies: Identifying Hits and Lead Optimization:
    • High-throughput screening (HTS) and structure-based drug design (SBDD) are commonly employed to screen macrocyclic peptidomimetic libraries.
    • Hits obtained from initial screenings undergo optimization, including structural modifications, to improve binding affinity, selectivity, and drug-like properties.
    • Iterative cycles of screening and optimization aim to identify potent leads for further development.
  5. Beyond Peptide Mimicry: Expanding the Chemical Space:
    • Library design can explore beyond classical peptide mimics and incorporate non-peptidic moieties to expand the chemical space and maximize target coverage.
    • These non-peptide elements can provide additional opportunities for improved pharmacokinetics, oral bioavailability, and cell permeability.
  6. Computational Approaches: Accelerating Library Design and Hit Identification:
    • Computational methods, such as molecular docking, molecular dynamics simulations, and machine learning algorithms, play a vital role in predicting macrocycle binding and aiding library design.
    • These computational tools enable rational design, virtual screening, and hit identification, guiding the selection and synthesis of macrocyclic peptidomimetics.


The design and synthesis of macrocyclic peptidomimetic libraries offer a valuable resource for drug discovery efforts. Leveraging the structural diversity and unique properties of macrocycles, researchers can explore novel chemical space and target protein-protein interactions, receptor signaling, and enzyme activities. Advancements in synthetic methods, screening technologies, and computational approaches have paved the way for the efficient generation and identification of hits in macrocyclic peptidomimetic libraries. As these libraries continue to expand and evolve, they hold great promise for the discovery and development of next-generation therapeutics with enhanced pharmacological properties and target specificity.