A general approach for retrosynthetic molecular core analysis.

Area of Science:

• Computational Chemistry
• Cheminformatics
• Medicinal Chemistry

Background:

• Scaffold analysis is a key method for understanding chemical space and structure-activity relationships (SAR).
• Analog series-based scaffolds (ASBS) represent synthetically relevant core structures for analog series.
• Current methods often use a 'single molecule-single scaffold' approach, limiting comprehensive analysis.

Purpose of the Study:

• To develop a general conceptual framework for scaffold analysis that considers all putative cores within a compound data set.
• To move beyond the traditional 'single molecule-single scaffold' correspondence.
• To provide a versatile methodology for various applications in chemical data analysis.

Main Methods:

• Defined a 'putative core' as a significant molecular substructure reachable via retrosynthesis rules.
• Constructed a bipartite network of molecules and their putative cores.
• Utilized this network to identify analogs and analyze scaffold diversity and structure-property relationships.

Main Results:

• Demonstrated a general framework for scaffold analysis by constructing molecule-core networks.
• Illustrated applications including inter- and intra-core diversity analysis and identification of analog series.
• Showcased potential for structure-property relationships and analog searching.

Conclusions:

• The presented molecule-core network is a general methodology applicable to diverse scaffold analysis tasks.
• This framework softens the 'single molecule-single scaffold' limitation, enabling richer insights.
• Future statistical methods are envisioned to draw quantitative conclusions from these networks.