Revisiting Pyrimidine-Embedded Molecular Frameworks to Probe the Unexplored Chemical Space for Protein-Protein...

Area of Science:

• Medicinal Chemistry
• Chemical Biology
• Drug Discovery

Background:

• Protein-protein interactions (PPIs) are crucial in biology and disease but are challenging drug targets.
• Existing chemical libraries are ill-suited for modulating PPIs due to their unique binding characteristics.
• There is a need for novel strategies to expand the druggable chemical space for PPI modulation.

Purpose of the Study:

• To develop a diversity-oriented synthesis strategy for creating novel chemical scaffolds targeting PPIs.
• To generate maximal skeletal diversity using a privileged substructure approach.
• To explore new avenues for drug discovery beyond traditional targets.

Main Methods:

• Developed a privileged substructure-based diversity-oriented synthesis (pDOS) strategy.
• Utilized pyrimidine as a privileged substructure for generating diverse polyheterocycles.
• Employed tandem cyclizations, diverse pairing strategies, and skeletal transformations.
• Designed peptidomimetics and identified allosteric inhibitors of ACE2-RBD interaction.

Main Results:

• Generated 39 distinct pyrimidine-embedded frameworks with significant molecular and 3D structural diversity.
• Validated diversity using chemoinformatic analyses (Tanimoto similarity, PMI).
• Demonstrated the ability to target previously undruggable PPIs with novel scaffolds.

Conclusions:

• The pDOS strategy effectively creates structurally diverse polyheterocycles targeting PPIs.
• This approach expands the chemical space for modulating complex protein interfaces.
• The pyrimidine-based scaffolds offer a promising platform for discovering novel therapeutics for challenging targets.