Heteroaromatic rings of the future

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Small aromatic ring systems are crucial for designing new synthetic protein ligands.
• A comprehensive catalog of these structures is essential for drug discovery and development.
• Existing databases lack a complete inventory of potential heterocyclic scaffolds.

Purpose of the Study:

• To create a comprehensive virtual library of small aromatic ring systems.
• To identify and quantify the number of synthesized versus unsynthesized heterocyclic compounds.
• To stimulate research by highlighting tractable, yet unexplored, heterocyclic structures.

Main Methods:

• Generation of a complete list of 24,847 small aromatic ring systems, termed the Virtual Exploratory Heterocyclic Library (VEHICLe).
• Substructure searches of literature and compound databases to identify synthesized compounds.
• Application of a validated machine learning model to estimate the number of synthetically tractable, unpublished ring systems.

Main Results:

• The VEHICLe database contains 24,847 unique small aromatic ring systems.
• Only 1701 of these systems have been reported in the literature or databases.
• Machine learning predicts over 3000 additional synthetically tractable, yet unpublished, ring systems.
• The publication rate for novel examples is low, estimated at 5-10 per year.

Conclusions:

• A vast majority of potential small aromatic ring systems remain unexplored.
• Significant opportunities exist for the synthesis of novel heterocyclic compounds for protein ligand development.
• This work provides a valuable resource and highlights untapped areas for synthetic chemists.